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NDT Advance Access published online on August 22, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn467
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Enhanced clearance of highly protein-bound drugs by albumin-supplemented dialysate during modeled continuous hemodialysis

Mariann D. Churchwell1,2, Deborah A. Pasko2,3, William E. Smoyer2,4 and Bruce A. Mueller2,5

1 Department of Pharmacy Practice, University of Toledo College of Pharmacy, Toledo, OH 2 Renal Replacement Therapy Kinetics Study Group (RRTKSG) 3 Pediatric Nephrology Division, C.S. Mott Children's Hospital, Ann Arbor, MI 4 Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH 5 Department of Clinical, Social and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, MI, USA

Correspondence and offprint requests to: Mariann D. Churchwell, Department of Pharmacy Practice, The University of Toledo College of Pharmacy, 2801 W. Bancroft 609, Toledo, OH 43606-3360, USA. Tel: +1-419-530-2198; Fax: +1-419-530-1950; E-mail: mariann.churchwell{at}utoledo.edu; mdchurchw{at}comcast.net



   Abstract
Top
 Abstract
Background
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 
Background. In 2006, there were 16 796 toxic exposures attributed to valproic acid (VPA), carbamazepine (CBZ) and phenytoin (PHT) reported to the US Toxic Exposure Surveillance System. Of these, 30% (5046) were treated in a health care facility with 12 cases resulting in death. These drugs are highly protein bound and poorly dialyzable; however, it has been suggested that albumin-supplemented dialysate may enhance dialytic clearance. We investigated whether the addition of albumin to dialysate affects dialytic clearance of VPA, CBZ and PHT.

Methods. VPA, CBZ and PHT were added to a bovine blood-based in vitro continuous hemodialysis circuit, which included a polysulfone or an AN69 hemodialyzer. VPA, CBZ and PHT clearances were calculated from spent dialysate and pre-dialyzer plasma concentrations. VPA, CBZ and PHT clearances with control (albumin-free) dialysate were compared to clearances achieved with 2.5% or 5% human albumin-containing dialysate. The influences of blood flow (180 and 270 mL/min) and dialysate flow (1, 2 and 4 L/h) on dialysis clearance were also assessed.

Results. The addition of 2.5% albumin to dialysate significantly enhanced dialytic clearance of VPA and CBZ, but not PHT. Use of 5% albumin dialysate further increased VPA and CBZ clearance. Overall, drug clearance was related directly to dialysate flow but independent of blood flow.

Conclusion. Continuous hemodialysis with albumin-supplemented dialysate significantly enhanced VPA and CBZ, but not PHT, clearance compared to control dialysate. Continuous hemodialysis with albumin-supplemented dialysate may be a promising therapy to enhance dialytic clearance of selected highly protein-bound drugs.

Keywords: albumin dialysate; carbamazepine; CVVHD; phenytoin; valproic acid



   Background
Top
 Abstract
 Background
Materials and methods
 Results
 Discussion
 Conclusion
 References
 
The 2006 Toxic Exposure Surveillance System (TESS) reported 16 796 toxic exposures resulting in 12 deaths attributed to valproic acid (VPA), carbamazepine (CBZ) and phenytoin (PHT) [1]. TESS is a comprehensive poisoning surveillance database in the United States compiled by the American Association of Poison Control Centers. This database was developed in 1983, and contains detailed toxicological information on >43 million human exposures and includes >2.4 million reports from 61 US poison centers for 2006 alone [1].

Intermittent hemodialysis can be a useful treatment for selected drug intoxications. When a high permeability hemodialyzer is used, dialytic drug removal is dependent upon drugs having a favorable pharmacokinetic profile, including a molecular weight of <2000 Da, protein binding rates <50%, volume of distribution <0.75 L/kg and high water solubility [2]. For drugs such as aspirin, lithium, theophylline and phenobarbital, which have these pharmacokinetic characteristics, hemodialysis is an effective treatment for drug clearance and reduced toxicity in cases of drug overdoses [1,2]. In contrast, extracorporeal removal of drugs with less favorable pharmacokinetic profiles has not been found to be very effective and consequently alternative treatments or specific antidotes have been developed [2]. Intoxications with agents that have limited potential for removal by standard extracorporeal therapies are common and present significant challenges to clinicians faced with treating these patients.

In the United States, VPA was responsible for 8627 toxic exposures in the most recent year available (2006) with 1915 (22%) patients requiring treatment in a health care facility. Of those receiving care in a health care facility, 72 (3.8%) patients were considered to have had a major event, and 1 death was reported [1]. Among children, VPA use resulted in 1323 toxic exposures, with 554 (42%) of the reported cases in children 6 years of age or younger [1]. VPA's molecular weight (MW) is 144 Da, volume of distribution (Vd) ~13 L, has a strong affinity to albumin and is 80–90% protein bound [3]. However, VPA's protein binding becomes saturated once supratherapeutic serum concentrations are reached [4]. Supratherapeutic serum concentrations increase the percentage of unbound VPA and lead to its enhanced clearance during standard intermittent hemodialysis [4–8].

CBZ was responsible for 4357 toxic exposures in the United States in 2006 with 1497 (34%) patients requiring treatment in a health care facility. Of those treated in a health care facility, 95 (6.3%) patients were considered to have had a major event with two deaths reported [1]. Of the reported CBZ toxic exposures to TESS, CBZ use resulted in 1120 toxic exposures in children with 691 (61.7%) of the reported cases in children age 6 years or younger [1]. CBZ with a MW of 236 Da, Vd 0.8–1.4 L/kg and is highly protein bound (~75%) to albumin and alpha-1 acid glycoprotein [9]. Only 40–50 mg of CBZ is removed during a 4-h conventional hemodialysis treatment using older, less permeable dialyzers [10]. The use of more permeable hemodialyzers results in a higher CBZ clearance rate [11,12]. Charcoal hemoperfusion has been reported to reduce CBZ serum concentration by 30–40% in CBZ overdose [13]. However, the availability of charcoal hemoperfusion therapy is limited [14].

PHT was responsible for 3812 toxic exposures in the United States in 2006 with 1634 (42.9%) patients requiring treatment in a health care facility. This resulted in 50 (3.1%) patients treated in a health care facility considered to have had a major event, with nine deaths reported [1]. There were 475 reports of toxic exposure from PHT in children, with 344 (72%) of these reported cases in children 6 years of age or younger [1]. PHT has a MW of 272 Da, Vd 0.7 L/kg, a strong affinity to albumin with ~90% protein bound although slightly less so (~80%) in patients with chronic kidney disease [15]. PHT is not considered to be ‘dialyzable’ because of this pharmacokinetic profile; however, reports of partial PHT hemodialytic clearance with high permeability hemodialyzers have been published [16,17]. Charcoal hemoperfusion may be an option with selected patients [18].

We hypothesized that the addition of albumin to dialysate would enhance clearance of drugs that are highly bound to albumin. To test this hypothesis, we prepared albumin-based dialysates, with differing albumin concentrations, and used them in an in vitro continuous hemodialysis circuit to analyze the ability of alterations in dialysate albumin content, as well as dialysis operating characteristics, to influence dialytic clearance of the highly protein-bound drugs VPA, CBZ and PHT.



   Materials and methods
Top
 Abstract
 Background
 Materials and methods
Results
 Discussion
 Conclusion
 References
 
The continuous hemodialysis model used 1 L of pH-regulated, bovine blood (Animal Technologies, Tyler, TX, USA) anticoagulated with 3.8% sodium citrate, placed in a 2 L Erlenmeyer flask which was submerged in a 37°C water bath and continuously stirred [19]. The average bovine blood albumin was 3.0–3.3 g/dL.

VPA [Valproate for injection, United States Pharmacopeia (USP)] was added to the bovine blood at a concentration of 100 mg/L. The VPA concentration of 100 mg/L was based on the upper end of the usual therapeutic serum concentration range of 50–100 mg/L.

Carbamazepine 2-hydroxypropyl-β-cyclodextrin complex (CBZ HBC, Sigma, St. Louis, MO, USA) was reconstituted according to the manufacturer's recommendation using 0.384 g of CBZ HBC complex reconstituted in 0.85 mL of saline by adding 0.4 mL of saline to the complex, stirring until the saline was saturated with the CBZ HBC, and then adding 0.1 mL of saline to the complex and repeating the process until the saline was completely added and the complex was fully in solution. The CBZ HBC complex was then added to the bovine blood at a concentration of 16 mg/L, which exceeds the usual therapeutic serum concentration range of 4–12 mg/L.

PHT for injection, USP was also added to the bovine blood at a concentration of 50 mg/L. The PHT concentration of 50 mg/L was based on what would be representative of a toxic serum concentration that exceeds the usual therapeutic range of 10–20 mg/L.

VPA, CBZ and PHT bovine blood concentrations exceeded or were at the upper limit of therapeutic range but were within the detectable limits of our assay. Urea (Sigma) was also added to the bovine blood to yield an initial blood urea nitrogen (BUN) concentration of 75 mg/dL and was used as a control to assess solute clearance.

B. Braun Diapact® continuous hemodialysis machines and B. Braun Diapact(TM) tubing kits were used for continuous hemodialysis circuits. The extracorporeal circuit was primed according to manufacturer's recommendations using heparinized 0.9% NaCl (5000 units heparin/L). Two different hemodialyzers were used in the experiments: polysulfone [Optiflux F-160 NR, Fresenius, (Lexington, MA) surface area 1.5 m2], and AN-69 [Multiflow M-60, Gambro/Hospal, Lakewood, CO; surface area 0.6 m2]. Once the circuit was primed, the solutes were added to the blood. This blood was recirculated through the CRRT system for 20 min prior to the start of the experiment to allow for coating of the tubing and hemodiafilter by blood proteins [20].

This study consisted of three arms with each arm using a different percentage of albumin dialysate supplementation. The control arm used dialysate containing 0% albumin, while the two treatment arms used 2.5% and 5.0% albumin-supplemented dialysate, respectively.

Control dialysate was prepared by adding 240 mL of NormocarbTM sterile bicarbonate renal dialysis concentrate (Dialysis Solutions, Inc., Richmond Hills, Ontario, Canada) to a 3 L bag of sterile water (Abbott Laboratories, Chicago, IL, USA). The first treatment arm required the addition of 374.4 mL albumin [(Human) USP, 25% solution (Baxter Healthcare Corp., Westlake, CA, USA)] to the prepared 3370 mL of Normocarb(TM) dialysate to yield a final albumin concentration of 2.5%. The second treatment arm required the addition of 842.5 mL of albumin [(Human) USP, 25% solution] to the prepared 3370 mL of Normocarb dialysate(TM) to yield a 5% albumin concentration.

The dialysate was run in a single-pass, countercurrent method for this continuous hemodialysis model [19,21]. The dialysate flow rates (Qd) were 1 L/h, 2 L/h and 4 L/h, and the ultrafiltration rate was set at zero. Experiments were run with a blood flow rate (Qb) initially set at 180 mL/min for each of the three Qd. Experiments were then repeated with a Qb of 270 mL/min at each Qd.

Continuous hemodialysis was run at each Qb and Qd setting allowing adequate time (3–10 min) for spent dialysate to be produced at the requisite rates before samples were obtained. For each arm of the study, both hemodiafilters were tested at two different Qb for all three different Qd. Blood and dialysate samples were obtained for each Qb and Qd combination. Blood samples were obtained from the pre-hemodialyzer sampling port and spent dialysate samples from the spent dialysate sampling port. This process was repeated five times with each hemodialyzer type, using a new hemodialyzer and extracorporeal circuit each time.

VPA, CBZ, PHT and urea concentrations were assayed from blood samples obtained at the pre-filter port (A) and the spent dialysate (D) samples from the spent dialysate sampling port of the Diapact(TM) continuous venovenous hemodialysis (CVVHD) circuit. Blood samples were transferred to Vacutainer(TM) (Becton Dickinson, Franklin Lakes, NJ, USA) red top blood collection tubes and centrifuged at 3000 rpm for 30 min. The plasma was transferred to cryovials (Fisher Scientific, Pittsburgh, PA, USA) by a pipette and stored at –80°C until the time of assay.

VPA, CBZ and PHT and BUN concentrations were analyzed by fluorescence polarization immunoassay (FPIA) with a COBAS Integra® 400 Plus (Roche Diagnostics, Indianapolis, IN, USA). The lower limit of detection for VPA was 2.4 µg/mL, CBZ was 0.11 µg/mL, PHT was 0.42µg/ mL and BUN was 1.8 mg/dL.

Calculations
The fraction of VPA, CBZ, PHT and urea that crossed the hemodialyzer during continuous hemodialysis was expressed as the extraction coefficient (EC). To determine EC and transmembrane clearance (Cl) of each solute, the following equations were used.

Extraction coefficient (EC) = D/A

Continuous hemodialysis transmembrane clearance = EC x Qd where

A = solute plasma concentration obtained from the pre-hemodialyzer port

D = solute spent dialysate concentration obtained from the spent dialysate port

Qd = dialysate flow rate

Statistical analysis
Power analysis showed that a sample size of five hemodialyzers would detect a 25% difference in CBZ, PHT and VPA clearance between hemodialyzer types assuming a 10% standard deviation with a power of 0.9 and a significance level of P < 0.05. The clearance data were analyzed using single-factor ANOVA to compare the EC of each drug between the standard dialysate (control) arm and the albumin-based dialysate (treatment) arms at the same Qb and Qd in continuous hemodialysis mode for each hemodialyzer type.



   Results
Top
 Abstract
 Background
 Materials and methods
 Results
Discussion
 Conclusion
 References
 
All experiments were run according to the protocol as described in the Methods section and no circuit failures occurred. The urea EC for the AN69 hemodialyzer ranged from 0.72 to 1.01. The F-160 hemodialyzer urea EC ranged from 0.76 to 1.10. A decrease in the urea EC was noted with the addition of albumin to dialysate for both hemodialyzer membranes but generally this decline was not statistically significant (Table 1). Spent dialysate concentrations of all study drugs exceeded the assay's lower limit of detection in all experiments, indicating that all drugs were cleared by continuous dialysis.


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  		Table 1 Urea extraction coefficient (EC)—AN69 and polysulfone hemodialyzers

 
The addition of albumin to the dialysate consistently increased VPA EC and 5% albumin dialysate tended to have a higher EC than the 2.5% albumin dialysate EC values (Table 2). Changes in Qb or Qd did not have a consistent or significant effect on VPA EC. In general, the larger polysulfone hemodialyzer tended to have a greater VPA EC than the AN69 hemodialyzer when all dialysis-operating characteristics were held constant.


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  		Table 2 Valproic acid extraction coefficient (VPA EC)—AN69 and polysulfone hemodialyzers

 
The CBZ EC tended to increase with the addition of albumin to dialysate (Table 3). In four of the 12 blood flow/dialysate flow/dialyzer combinations, the 5% albumin dialysate resulted in a significantly higher EC than was seen with the 2.5% albumin dialysate. As with the other drugs, no consistent effect on CBZ EC was noted with changes in Qb. Increasing Qd tended to lower the CBZ EC regardless of dialysate type, particularly with the AN69 hemodialyzer. The CBZ EC using control dialysate did not differ much between filter types, regardless of Qb and Qd. Interestingly, the CBZ EC values between filter types differed considerably once albumin was added to the dialysate. At low Qd with albumin-containing dialysates, the AN69 CBZ EC trend was higher than those generated with the polysulfone dialyzers, but at higher Qd with albumin-containing dialysates; the CBZ EC were considerably higher with the polysulfone hemodialyzers.


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  		Table 3 Carbamazepine extraction coefficient (CBZ EC)—AN69 and polysulfone hemodialyzers

 
Overall, the addition of albumin to dialysate tended to lower PHT EC in contrast to our hypothesis (Table 4). Increasing Qb tended to increase PHT EC with the control dialysate; however, changes in Qb had no consistent influence once albumin was added to dialysate. Increasing the Qd had no consistent effect on PHT EC. When control dialysate was used, the PHT EC was consistent and did not differ between dialyzer types. Albumin added to dialysate resulted in the larger polysulfone hemodialyzer having substantially higher PHT EC than the AN69 hemodialyzer at any blood and dialysate flow rate combinations.


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  		Table 4 Phenytoin extraction coefficient (PHT EC)—AN69 and polysulfone hemodialyzers

 
Changes in EC must be considered in conjunction with the Qd to determine overall drug clearances achieved with each of the studied continuous hemodialysis combinations Figures 1GoGoGoGo–6 depict the drug clearances achieved with each of the Qd, Qb, dialyzer types and drugs used in this study. For VPA and CBZ, increasing Qd substantially increased clearance, whereas increasing Qb from 180 mL/min to 270 mL/min had a marginal effect. Increasing albumin dialysate concentration consistently increased VPA and CBZ transmembrane clearance. In contrast, the addition of albumin to dialysate did not enhance PHT transmembrane clearance and indeed paradoxically reduced clearance in most experiments. Increasing Qd was the most reliable way to increase PHT transmembrane clearance. For VPA and CBZ, albumin dialysate increased clearance to higher degrees with the polysulfone dialyzers than with the AN69 hemodialyzers. PHT transmembrane clearance tended to be lower with the AN69 than the polysulfone hemodialyzer, especially in the presence of albumin dialysate or at higher Qd.


Figure 1
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  		Fig. 1 Valproic acid clearance M-60 hemodialyzer. The y-axis represents the clearance of each drug in mL/min, the x-axis is the percent concentration of albumin in the dialysate and the blood flow rate (Qb) in mL/min and the z-axis is the dialysate flow rate (Qd) in L/h.

 

Figure 2
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  		Fig. 2 Carbamazepine clearance M-60 hemodialyzer. The legend is the same as for Figure 1.

 

Figure 3
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  		Fig. 3 Phenytoin clearance M-60 hemodialyzer. The legend is the same as for Figure 1.

 

Figure 4
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  		Fig. 4 Valproic acid clearance F-160 hemodialyzer. The legend is the same as for Figure 1.

 

Figure 5
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  		Fig. 5 Carbamazepine clearance F-160 hemodialyzer. The legend is the same as for Figure 1.

 

Figure 6
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  		Fig. 6 Phenytoin clearance F-160 hemodialyzer. The legend is the same as for Figure 1.

 


   Discussion
Top
 Abstract
 Background
 Materials and methods
 Results
 Discussion
Conclusion
 References
 
This study was designed to determine whether the addition of albumin to dialysate would increase the transmembrane clearance of highly protein-bound drugs and did not determine if any drug adsorption occurred to either hemodialyzer membrane types. Our results demonstrated that the VPA and CBZ dialytic clearance can be enhanced with albumin-supplemented dialysis. These results suggest that continuous hemodialysis conducted with albumin-supplemented dialysis could be an adjunctive therapy in critically ill patients with severe VPA or CBZ intoxications.

Albumin-supplemented dialysate has been used in the treatment of patients with liver failure [22,23]. Many of the accumulated toxins in liver failure are highly protein bound and are not dialyzable with conventional hemodialysis techniques. The addition of albumin to the dialysate side of hemodialyzer membrane may enhance the clearance of protein bound toxins. Basic thermodynamic principles of protein-binding affinity and solute movement along a concentration gradient explain the technique. Dialysate-side albumin acts as a ‘sink’ to bind any free toxin that crosses the dialyzer membrane with a concentration gradient from the blood to the dialysate side [24]. As soon as the toxin binds to the dialysate-side albumin, the concentration gradient is restored and more blood-side toxin will disassociate from blood-side albumin, cross the membrane into the dialysate and then bind to dialysate-side albumin. These toxins are then removed from the system; consequently, there is a net loss of toxins from the patient [23].

Many different approaches to bound solute dialysis are being researched and not all of them use albumin as the binder in the dialysate. The most commonly described are the molecular adsorbent recirculating system (MARS), Prometheus and Biologic-DT [25]. The most basic system is the one we used in this trial, single-pass dialysate within a CVVHD system. Albumin dialysis has been used to lower ammonia and bilirubin in liver failure patients [26–28] and remove copper in patients with Wilson's disease [29–31]. Copper and bilirubin are solutes that are not appreciably dialyzed with conventional hemodialysis.

Askenazi [32] published a case report of applying albumin dialysis in a 30 kg pediatric patient with CBZ intoxication. These authors used CVVHD with a 4.5% albumin dialysate using an AN69 M60 hemodialyzer (same hemodialyzer used in the present study). Serum CBZ concentrations declined substantially but the patient had also received repeated doses of activated charcoal therapy. Direct CBZ dialytic clearance was not measured in this case report. The authors suggested albumin dialysate enhanced CBZ clearance and that the cost of an albumin-based dialysate was offset by the decreased ICU stay for this patient. Pasko et al. used albumin dialysis to treat a critically ill patient with methotrexate toxicity [33]. In this case report, the addition of albumin appeared to accelerate methotrexate removal compared with conventional CVVHD.

These reports led us to conduct the present study. By carefully controlling blood and dialysate flow rates, albumin concentration and filter type, we were able to determine how these factors interact and contribute to dialytic drug clearance. Our findings of accelerated CBZ clearance with the addition of albumin to dialysate are consistent with the report that suggested that CBZ half-life was accelerated during CVVHD with a 4.5% albumin dialysate [30]. In that report, Askenazi concluded that albumin dialysate might accelerate removal of other highly protein-bound drugs [30]. Indeed, this was true in our study with CBZ as well as VPA. The addition of 2.5% albumin to dialysate significantly increased VPA and CBZ clearance and increasing the albumin to 5% further increased dialytic clearance in many cases. However, we were surprised to find that this trend did not hold for PHT. Another permutation of albumin dialysis that includes a charcoal filter, MARS, has been reported to successfully treat PHT toxicity [34]. Actual MARS PHT clearance was not calculated in this case report but the serial PHT serum concentrations declined markedly during MARS treatment. In our study, the addition of albumin to dialysate did not enhance PHT dialytic clearance. In fact when the M60 hemodialyzer was used, PHT clearance was substantially impaired compared to albumin-free dialysate. Because the data were in such contrast to our VPA and CBZ findings, these samples were assayed a second time with identical results.

It is difficult to reconcile why our study yielded significantly enhanced VPA and CBZ clearance and significantly reduced PHT clearance. Potential answers may include a charge interaction between PHT and albumin dialysate or some unknown membrane effect. Given that the effect was seen to a similar degree with both 2.5% and 5% albumin concentrations, it appears that the effect is caused by the presence of albumin in the dialysate and not necessarily the concentration of albumin in the dialysate.

Our continuous hemodialysis model [19,21] used bovine blood with human albumin in the dialysate. An interspecies difference in drug binding and affinity may well exist. Differences in protein-binding affinity could affect dialytic clearance values in bound solute dialysis [35]. Clearly these data need corroboration in the clinical setting. Although intuitively, we would have agreed with Askanazi's suggestion that albumin dialysis should be effective in enhancing the clearance of many highly protein-bound drugs, our PHT findings suggest that there may be exceptions.

Figures 1–6 provide clearance information beyond the influence of albumin in the dialysate. Clearly, the addition of albumin influences drug clearance in many cases. However, when contrasting Figures 1–3 with Figures 4–6, it becomes readily apparent that the choice of hemodialyzer is more important than whether albumin is added to the dialysate. The use of the larger and more permeable polysulfone hemodialyzer results in far greater clearance than that of the AN69 hemodialyzer at almost every Qb, Qd and albumin concentration combination. Further, it becomes apparent that the use of high dialysate flow rates increased overall clearance, independent of what happened to the EC. These observations should guide the clinician considering the use of continuous hemodialysis or albumin dialysate in the treatment of these intoxications.



   Conclusion
Top
 Abstract
 Background
 Materials and methods
 Results
 Discussion
 Conclusion
References
 
VPA and CBZ dialytic clearance can be enhanced significantly with the addition of albumin to dialysate. This confirms an earlier case report for CBZ [32] and provides proof of concept for VPA removal by albumin dialysis. Albumin concentration, dialysate flow rate and choice of hemodialyzer type all significantly affect drug clearance. In contrast, PHT dialytic clearance was decreased with the addition of albumin to dialysate. These findings have implications where albumin dialysis is being considered for the treatment of intoxication of highly protein-bound drugs particularly these three anti-seizure medications that have been associated with substantial morbidity and mortality.



   Acknowledgments
 
This manuscript was supported in part by a grant from the C. S. Mott Children's Hospital. The authors acknowledge the contributions of Jason Blythe, Stephanie Kaucher, Carla Freshwater and James M. Stevenson in conducting these experiments. These data were presented in poster form at the International Conference on Continuous Renal Replacement Therapy in San Diego, CA, February 2005 and the American Society of Nephrology Renal Week 2005 meeting in Philadelphia, PA, USA.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Background
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 

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Received for publication: 7. 2.08
Accepted in revised form: 24. 7.08


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