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A hemodialysis patient suffered from circulation failure due to a low output syndrome caused by a hyperkalemia (9.9 micromol/l) with typical ecg signs. An emergency hemodialysis was started. After 2 h ecg signs of hypokalemia (2.1 micromol/l) were detectable. Hemodialysis was stopped. 2 h later, serum potassium rose to 6.2 micromol/l. An obturation of the aorta and the inferior caval vein with perfusion through collateral vessels of the lower body side was obvious, resulting into a faster electrolyte correction in the upper and a delayed correction in the lower body side with a rebound in the upper compartment. Dialysis time and dialysate potassium (4.0 micromol/l) were increased. Furthermore no potassium problems occurred.

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Methothrexate (MTX) causes unwanted adverse events by affecting gastrointestinal and bone marrow cells when used as an immunosuppressant. Our aim was to reduce those side effects by covalent binding of methothrexate to human serum albumin (HSA) targeting rapidly proliferating lymphocytes, which are known to ingest albumin as an energy source. Twenty-one rats received a kidney transplant. Group A (n = 5) received standard immunosupression (free MTX); group B (n = 9), albumin-MTX conjugates; and group C (n = 7) albumin control. The primary endpoint of this animal study was transplant survival, which was evaluated as death due to uremia. The study was terminated on day 100. Placebo-treated rat recipients (group C) rejected their grafts at a median of 8 days, which was prolonged to 17 days in standard immunosuppressed rats (group A), resulting in doubling transplant survival compared to nonimmunosuppressed animals. However, the same dose given as HSA-conjugated MTX prolonged the median survival time to 43 days. (group B). Hence, the administration of conjugated methotrexate appeared to result in a doubling of transplant survival compared with standard immunosuppression. Moreover, two animals receiving MTX-HSA became long-term survivors without additional immunosuppression. Further studies should be performed to evaluate the significance of these findings in larger animals and possibly in clinical studies.

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Extracorporeal liver support methods have been tested for over 50 years now. Standard techniques of blood purification like dialysis, adsorption, hemo- and plasma filtration as well as bioreactor-based approaches using liver cells or tissues have been used. Most clinical experience, however, is limited to use in acute liver failure (ALF). Since 1993, the Molecular Adsorbent Recirculating System (MARS) has been used clinically -- a system that combines dialysis, filtration and adsorption in a biocompatible method. Human serum albumin (HSA) acts as a selective molecular adsorbent binding protein-bound compounds like bile acids or bilirubin. These substances can contribute to the maintenance or even further aggravation of liver failure. They are linked with the pathogenesis of hyperdynamic hypotonic circulation, hepatic encephalopathy, hepatorenal syndrome, impaired hepatic protein synthesis, and intractable pruritus seen in chronic liver failure. HSA takes over the toxic substances from a patient's blood and passes through a remote detoxification process including bicarbonate-dialysis and a two-step adsorption. It is then recirculated in the patient's blood. Up to today, more than 4000 patients have been treated in approximately 16,000 single sessions. Thus, MARS represents the most frequently used liver support method at the present time. In addition to ALF, mainly acute decompensations of chronic liver failures (ACLF) have been treated. The impact of the extracorporeal treatment on relevant medical parameters of intensive care medicine is discussed with regard to the specific situation of the liver-failure patient (susceptibility to infection, atypical picture and course of infection, coagulation disorders and bleeding tendencies).

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Albumin dialysis using the Molecular Adsorbents Recirculating System (MARS) has been found to be beneficial in the treatment of cirrhotic patients with acute decompensation to improve survival as well as reduce associated complications. The present study attempts to analyze the costs involved, and compare it to the benefit as a result of the MARS therapy, thus evaluating its cost-effectiveness. Using the results of a study by Kim et al. describing the effects of complications on the cost of hospitalization in alcoholic liver disease patients, the expenditure incurred in a group of 11 patients treated with standard medical therapy (five survivors) and a group of 12 patients treated with MARS in addition (11 survivors) (Heemann et al., Hepatology 2002) were analyzed. MARS resulted in a reduction of in-hospital deaths, as well as liver disease-related complications. Both these factors led to a substantial reduction of costs in the MARS group, which was enough to counterbalance the extra costs associated with extra-corporeal therapy. In the control group, the total hospitalization cost per survivor were calculated to be at $35,904. In the MARS group, the overall expenditure per survivor including standard medical therapy plus additional MARS liver support therapy were $32,036--a saving of nearly $4000 compared to the control group. Therefore, it appears that the benefits of MARS therapy are enough to justify the cost of treatment and safe hospital costs, at least in the described population. However, further studies are needed to confirm these results.

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UNLABELLED: Albumin dialysis with the MARSystem is used in many hospitals to support excretory hepatic function in acute or acute on chronic liver failure. Potential pathogenic albumin bound substances accumulated in excretory liver insufficiency can be removed from patients blood by dialysis against albumin solution. A specific membrane enables the selective transport of albumin bound metabolites to the albumin containing dialysate compartment, where the loaded transport albumin is cleared and regenerated at the same time by adsorption columns and a second dialyser. Between 1993 and 1995 different membranes, set-ups and components in albumin dialysis were tested and led finally to the recirculating MARSystem with a modified polysulphone based membrane (P3/5S Gambro, Hechingen) and two adsorption columns (N350 and BR 350, ASAHI Medical Ltd.), which showed the best performance at this time. This first generation of MARSystems was used clinically between 1995 and 1998 with only minor changes in 15 patients with acute (n = 1) or acute deterioration of chronic liver disease in our department until the improved next generation of MARSystems has been available (MARS set and monitor, Teraklin AG, Rostock, Germany). Changes in blood tests pre/post during 95 single MARS treatments and in clinical status over treatment period were evaluated retrospectively. RESULTS: A significant decrease of albumin bound substances (average reduction during single MARS treatments: bilirubin -18%, bile acids -43.7%) as well as of water soluble metabolites (creatinine -32%, urea -31%) was observed. During extracorporeal therapy also a significant drop in platelets (- 15.4%) and a prolongation of activated prothrombin time (- 21%) was documented, whereas haemoglobin, WBC, electrolytes as well as transaminases and albumin were not affected significantly. CONCLUSION: Albumin dialysis with the first generation of MARS enables the removal of albumin bound and water soluble toxins. Unwanted side-effects and changes in laboratory tests are comparable to conventional haemodialysis (drop of platelets and prolongation of coagulation tests). The elimination of albumin bound and water soluble substances was accompanied by an improvement of clinical status.

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INTRODUCTION: Dysbalance between branched chain (BCAA) and aromatic amino acids (AAA), which can be quantified by a low Fischer's Index (SigmaBCAA/SigmaAAA), as well as elevated levels of free tryptophan in plasma are common in hepatic failure and may contribute to the development of hepatic encephalopathy. AIM: To evaluate the influence of a new extracorporeal detoxification system for liver failure (Molecular Adsorbents Recirculating System, MARS(R), i.e. dialysis against a recirculating albumin solution cleaned online by charcoal and an anion exchange resin) on plasma tryptophan and Fischer's Index. METHODS: Plasma samples were taken before, during and after MARS treatments (n = 11, mean blood flow 135 ml/min, mean dialysate flow 120 ml/min, high flux polysulfone membrane). Simultaneous to blood sampling, aliquots of the albumin dialysate were taken between the elements of the dialysate circuit. RESULTS: Fischer's Index in systemic blood increased during MARS by 24% (from 1.44 to 1.79, P < 0.001; mean treatment duration, 5.5 h). Systemic tryptophan level was significantly reduced at the same time (-25%, n = 8). Amino acid removal rates from plasma during a single dialyser passage ranged from 10 to 53%. In particular, AAA were preferentially removed (42-44% throughout treatment), while BCAA removal was 28-46% initially and later declined to 24-28%. A maximum concentration gradient between plasma and dialysate was maintained for the AAA throughout treatment through their apparently complete removal by the charcoal adsorber. Conversely, BCAA removal at both adsorbers was only minor. As a result, Fischer's Index showed a significant increase in the processed plasma, which became even more pronounced with increasing treatment duration. CONCLUSIONS: MARS enables an elevation of a pathologically decreased Fischer's Index as well as a reduction of systemic tryptophan levels in patients with liver failure. The effects of MARS on plasma amino acid dysbalance may contribute to an improvement of hepatic encephalopathy.

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The single pass albumin dialysis (SPAD) was reported to be an alternative to the Molecular Adsorbent Recirculating System (MARS) for the effective removal of protein bound substances in liver failure. Three SPAD experiments using different albumin concentrations and dialysate flow rates were performed. In each experiment, 1000 ml human donor plasma, spiked with 250 mg unconjugated bilirubin, 200 mg sulfobromophthalein (BSP) and 115 mg glycocholic acid (N-[3alpha,7alpha,12alpha-trihydroxy-24-oxycholan-24-yl]glycine) - a conjugated bile acid (BA), circulated in a closed loop with 150 ml/min and was dialysed against albumin solution. These substances are bound to the different binding sites of albumin and have different association constants. For the comparison, the standard MARS experiment was performed using the same plasma flow rate of 150 ml/min. Moreover, the clearances of bilirubin for MARS and SPAD during clinical treatments were calculated using own data and those reported by Seige, Kreymann, Jeschke, et al. in Transplant Proc 1999; 31: 1371-5. The concentrations of bilirubin, BSP and BA were measured in plasma and dialysate and for these substances clearances (Cl) were calculated. It is known that the elimination rate of bilirubin is not very high during albumin dialysis in comparison to other substances, like bile acids, due to the high association constant. An increase of albumin concentration or the flow rate improved the efficacy but also raised the costs substantially. In this study, we have shown that MARS is the more effective kind of albumin dialysis for the important substances like bile acids. By SPAD an improvement of efficacy can be reached only by dramatic increase of the costs. Also, the earlier experiments showed that MARS is safer because of the removal of the stabilizers, which are normally included in the commercial albumin solutions.

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Knowledge of factors associated with the detection of cutaneous malignant melanomas and reasons for delay in diagnosis are essential for the improvement of secondary prevention of cutaneous melanoma. For this reason, the extent and consequence of patient and professional delay in diagnosis and treatment was investigated in 233 patients with histologically proven primary cutaneous melanomas seen at the Department of Dermatology and Allergology at the Ludwig-Maximilians-University, Munich, Germany, between January 1999 and January 2001. Personal interviews were conducted by two physicians to obtain information on patients' knowledge of melanoma symptoms, sun behaviour, delay in seeking medical attention, professional delay and related factors. The main component of delay was patient related. Nearly one-third (29.2%) of all patients reported a delay interval of more than 12 months from the onset of an observed change in a pigmented lesion or first detection of a pigmented lesion to the first visit to a physician. The delay interval from the first visit to a physician to surgical treatment was shorter (< 1 month) in most of our patients (74.7%). The predominant symptoms of melanoma detected by patients were a change in colour and an increase in size or elevation. Most patients had obtained knowledge about cutaneous melanomas from television and magazines. A delay in diagnosis and a history of many sunburns and outdoor leisure time activities were not associated with a greater tumour thickness. However, fairer skin types, lower education levels and lack of knowledge about cutaneous melanoma were associated with a greater tumour thickness. Further efforts are necessary to improve public and medical education about early detection and prompt surgical treatment, which is known to be the most effective treatment modality for cutaneous melanomas.

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Biomaterials such as applied in microcapsules may have harmful effects on encapsulated cells. Up to now, there are no adequate assays available for testing the function and viability of cells in capsules. Therefore, we investigated whether the combination of MTS proliferation assay and live-dead viability assay is suitable for testing microencapsulated L929 fibroblasts in long-time culture. Proliferation of L929 cells was shown by a significant increase of formazan absorbance within the first 3 weeks (Day 0: 0.132 +/- 0.047; Day 7: 0.404 +/- 0.101; Day 14: 0.728 +/- 0.239; Day 21: 0.877 +/- 0.224) followed by stagnation and decrease thereafter. This was confirmed by an increasing proportion of dead cells measured by the live-dead assay. Thus, proliferation of encapsulated L929 can be reliably investigated by the MTS assay. In combination with life-dead assays, the proliferation can be correlated to the survival rate of the encapsulated cells.

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The Molecular Adsorbent Recirculating System (MARS) is a nonbiological liver support method based on the principles of dialysis, filtration, and adsorption. It allows the safe and efficient removal of both albumin-bound and water-soluble toxic metabolites, including ammonia, aromatic amino acids, tryptophan, and related phenolic and indolic products, as well as benzodiazepines. A well-documented effect of the treatment is the improvement of the hemodynamic situation of decompensated chronic patients. Systemic vascular resistance, mean arterial pressure, cerebral blood flow, and cerebral oxygen consumption increased significantly. The degree of hepatic encephalopathy decreased significantly. Increased intracranial pressure could be normalized in both chronic and fulminant liver failure. In three randomized clinical trials significant improvement of survival could be demonstrated. In a model of murine neuronal networks cultured on multi-microelectrode array plates and incubated with plasma from liver failure patients, a normalization of the spike and burst pattern could be observed, if plasma samples from MARS-treated patients before and after treatment were compared. In conclusion, MARS significantly improves central nervous system functions. It can serve as a model for the further investigation of the role of protein-bound substances in hepatic encephalopathy and cerebral hemodynamics.

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Liver support systems based on either dialysis, filtration, and adsorption or plasmaperfusion over hepatocytes have been tested clinically with varying success. A new approach in this field is the selective removal of albumin-bound end products of metabolism. This can be achieved in a high-flux dialysis setting by the addition of human serum albumin as a molecular adsorbent to the dialysate with subsequent recirculation of the dialysate over sorbents (molecular adsorbent recirculating system). The current knowledge about the albumin dialysis molecular adsorbent recirculating system is reviewed in this article.

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Long-term benefits of coronary angioplasty remain limited by the treatment-induced renarrowing of arteries, termed restenosis. One of the mechanisms leading to restenosis is the proliferation of smooth muscle cells. Therefore, proliferating cells of the injured arterial wall, which can be selectively transduced by retroviruses, are potential targets for gene therapy strategies. A direct single-dose therapeutic application of retroviral vectors for inhibition of cell proliferation is normally limited by too low transduction efficiencies. Encapsulated retrovirus-producing cells release viral vectors from microcapsules, and may enhance the transduction efficiency by prolonged infection. Primary and immortal murine and porcine cells and murine retrovirus-producing cells were encapsulated in cellulose sulphate. Cell viability was monitored by analysing cell metabolism. Safety, stability, transfer efficiency and extent of restenosis using capsules were determined in a porcine restenosis model for local gene therapy using morphometry, histology, in situ beta-galactosidase assay and PCR. Encapsulation of cells did not impair cell viability. Capsules containing retrovirus-producing cells expressing the beta-galactosidase reporter gene were implanted into periarterial tissue or a pig model of restenosis. Three weeks following implantation, beta-galactosidase activity was detected in the pericapsular tissue with a transduction efficiency of approximately 1 in 500 cells. Adventitial implantation of vector-producing encapsulated cells for gene therapy may, therefore, facilitate successful targeting of proliferating vascular smooth muscle cells, and allow stable integration of therapeutic genes into surrounding cells. The encapsulation of vector-producing cells could represent a novel and feasible way to optimize local retroviral gene therapy.

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Liver failure resulting from different causes and its concomitant complications represent difficult-to-treat conditions with high mortality rates, despite improved therapeutic modalities in intensive care medicine. The accumulation of albumin-bound metabolites that are normally cleared by the liver, such as bilirubin and bile acids, contributes substantially to the development of multiorgan dysfunction in these clinical situations. The molecular adsorbent recirculating system (MARS) represents a cell-free, extracorporeal, liver assistance method for the selective removal of albumin-bound substances. Moreover, it enables the removal of excess water and water-soluble substances via an inbuilt dialysis step. Since 1993, >400 patients have been treated in 53 centers in Europe, the United States, and Asia. Diseases treated with MARS included acute exacerbation of chronic hepatic failure, hepatorenal syndrome, acute hepatic failure, and primary nonfunction/poor function after liver transplantation and major liver resection. Treatments were well tolerated. No severe adverse events were observed. Six- to 8-h MARS treatments resulted in significant (P < 0.05) removal of bilirubin, bile acids, tryptophan, short- and middle-chain fatty acids, aromatic amino acids, and ammonia. Clearance rates for strongly albumin-bound substances were between 10 and 60 ml/min. The removal of albumin-bound toxins resulted in decreases in hepatic encephalopathy, increases in mean arterial pressure, and improvements in kidney and liver function. In the first randomized clinical trial of the MARS method for treatment of the hepatorenal syndrome, significant prolongation of survival was observed for the MARS-treated group. It is concluded that the MARS method can contribute to the treatment of critically ill patients with liver failure and different underlying diseases.

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Recently, significant improvement of renal function and prolongation of survival were reported in hepatorenal syndrome (HRS) patients treated with the Molecular Adsorbent Recirculating System (MARS). As no impact on extrarenal organ function was documented, this trial looked into multiple organ function changes during MARS in HRS patients. Eight HRS patients (4 male, mean age 42.1 years, range 30-58, all United Network for Organ Sharing [UNOS] status 2A) were treated intermittendly 4-14 times (total 47, mean 5.9 +/- 3.4) between 4 and 8 h/single treatment. The following changes were observed pre- and posttreatment: bilirubin 466 +/- 146 to 284 +/- 134 micromol/L, creatinine 380 +/- 182 to 163 +/- 119 micromol/L, urea 26.4 +/- 10.3 to 12.9 +/- 4.9 mmol/L, plasma sodium 127.5 +/- 7.7 to 137.5 +/- 4.8 mmol/L (all p < 0.01). Mean arterial pressure (MAP) increased from 71.9 +/- 12.8 to 95.6 +/- 7.8 Torr (p < 0.001). Oliguria or anuria, present in all patients, was successfully reverted. Ascites, present in all patients, was not detectable after the treatment period. The hepatic encephalopathy grade decreased from 2.8 +/- 0.8 to 0.8 +/- 0.7 (p < 0.0001). Child-Index decreased from 13.25 +/- 1.3 to 9.4 +/- 1.8 (p < 0.001). The hospital survival rate was 62%. One man underwent successful liver transplantation 18 months after the treatment. We conclude that MARS can improve multiple organ functions in patients with HRS.

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Neutrophils are critical effector cells in humoral and innate immunity and play a vital role in phagocytosis and bacterial killing. If they and/or their specific functions are lacking, then immunoparalysis may occur, and severe diseases like systemic inflammatory response syndrome (SIRS) or sepsis can take a fatal course. In this paper, we discuss the possibility of using preconditioned cells in an extracorporeal biohybrid immune support system. A human promyelocytic cell line was stimulated for different times with all-trans retinoic acid. The resulting cells displayed major signs and functions of mature neutrophilic granulocytes including oxygen radical production, phagocytosis of living and dead Escherichia coli, Staphylococcus aureus, Candida albicans, intracellular killing, and interleukin production. The cells can be expanded to yield a sufficient cell mass, and subsequent prestimulation results in an expression of specific neutrophil functions. Extracorporeal bioreactor experiments seem to be feasible to test the benefit in immunoparalysis-associated diseases like SIRS or sepsis.

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