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The management of acute renal failure in the critically ill patient is extremely variable and there are no published standards for the provision of renal replacement therapy in this population. Continuous renal replacement therapy seems to be the treatment of choice because of its superior metabolic and hemodynamic control. There is better organ protection by continuous treatment but no evidence for better survival or renal recovery due to continuous treatment. The debate about optimal membrane as well as about optimal dialysis dose is ongoing. An effluent flow rate of at least 35 ml/kg/h as well as lower BUN level at treatment initiation seem to be necessary to provide better survival rate. Peritoneal dialysis is a less suitable option in continuous renal replacement of the adult intensive care patient but hybrid methods such as extended daily dialysis and sustained low efficient daily dialysis need consideration with respect to continuous hemofiltration/dialysis., (Copyright 2003 S. Karger AG, Basel)

Lipoprotein(a) [Lp(a)] excess combined with hyperhomocysteinaemia and hyperfibrinogenaemia may contribute to the high incidence of vascular diseases in dialysis patients. This study is aimed at investigating the role of free apolipoprotein(a) [fapo(a)] in renal patients. We have been able to show that, as compared with controls (0.53 mg/l), the median serum concentrations of fapo(a) in patients with nephrotic syndrome (2.58 mg/l) and with peritoneal dialysis (3. 40 mg/l) were strongly elevated (5- to 7-fold), while the fapo(a) levels in patients undergoing haemodialyis (1.02 mg/l) and after renal transplantation (0.90 mg/l) were about doubled. The observed differences in fapo(a) levels indicate that several mechanisms may increase the level of fapo(a), i.e., reduced renal clearance, enhanced hepatic synthesis, or homocysteine releasing apolipoprotein(a) from Lp(a). In the study collective, the median total homocysteine levels were significantly elevated in all patient groups, stronger in patients on haemodialysis (31.4 micromol/l) and peritoneal dialysis (31.2 micromol/l) than in patients with nephrotic syndrome (19.7 micromol/l) and after renal transplantation (19.5 micromol/l). In transplant patients with adequate renal function and without other apolipoprotein(a)-increasing factors, fapo(a) was significantly increased when total homocysteine exceeded 22 micromol/l. In conclusion, our findings let us presume that an increased fapo(a) level in renal patients possibly could be one of the reasons contributing to the high incidence of vascular diseases in these patients, because fapo(a) not covalently linked with Lp(a) is even more easily able to inhibit the fibrinolytic system than the complete Lp(a). These preliminary results have to be confirmed by further investigations., (Copyright 2000 S. Karger AG, Basel)

Metabolic acidosis has been shown to act as a causative factor in muscle protein breakdown and negative nitrogen balance, as well as in decreased albumin synthesis. Albumin and other acute phase proteins (APP) are mainly synthesized in the liver following induction by interleukins, hormones and other mediators. Acute phase proteins have been shown to be predictors of cardiovascular mortality in the general population and in patients with end stage renal disease (ESRD). Clinical investigation gives evidence that albumin is reduced by acidosis in ESRD patients. The aim of our study was to investigate the role of the liver in acidosis, i.e. the influence of acidosis on metabolic activity and secretion of APP by liver cells (HepG2). Cells were cultured in a medium containing different amounts of bicarbonate. Metabolic activity was significantly diminished when the bicarbonate concentration of the extracellular medium was reduced (86.13+/-1.90% (pH 7.0) vs. 99. 53+/-90% (pH 7.4); p<0.01). While cellular release of negative APP was significantly decreased (albumin: 4.6+/-0.41 (pH 7.0) vs. 7.54+/-0.62 (pH 7.4) [ng/microg protein], p<0.001, transferrin: (0. 78+/-0.08 (pH 7.0) vs. 1.07+/-0.07 (pH 7.4) [ng/microg protein], p<0. 05), no significant influence of acidosis (pH 7.0) on the positive APP, alpha(1)-acid glycoprotein (AGP) (1.69+/-0.25) (pH 7.0) vs. 1.62+/-0.23 (pH 7.4) [ng/microg protein]), could be shown. Our data indicate that acidosis results in inhibition of liver cell metabolic activity and in reduced secretion of the negative acute phase proteins albumin and transferrin. In contrast, secretion of the positive acute phase protein AGP seems to be unchanged at pH 7.0 as compared to pH 7.4. We conclude that negative and positive APP in liver cells (HepG2) appear to be differently regulated by acidosis.

Metabolic changes in peritoneal dialysis (PD) patients are an important aspect concerning long-term outcome. Liver plays the main role in regulating metabolism. The effects of peritoneal dialysis fluids (PDF) on liver cell function are scarcely investigated. Therefore, we investigated the effects of PDF, different in some components, on liver cell metabolism in vitro. Metabolic activity (MTT), cell integrity (LDH release), proliferation (BrdU incorporation) and synthesis of albumin and transferrin are measured by incubating HepG2 cells for 3 h and 24 h with six different PDFs: (a) lactate-buffered, pH5.5: PDF I (1.5% gluc.); PDF II (4.5% gluc. ); (b) bicarbonate-buffered, pH7.4: PDF III (1.5% gluc.), PDF IV (4. 5% gluc.); (c) amino acid-based solutions, pH 7.4: PDF V (low AA level) and PDF VI (high AA level). Metabolic activity of bicarbonate-treated cells is greatly enhanced in comparison to lactate-buffered PDFs. These findings are confirmed by proliferation data. Synthesis of albumin and transferrin is significantly enhanced by amino acid-based solutions. Our data demonstrate, that lactate-buffered PDF impair liver cells much stronger than bicarbonate-buffered PDF. pH is the parameter which contributes to cytotoxicity and impaired metabolism to a major extent. In contrast to glucose-containing solutions, amino acid-based PDF stimulate protein synthesis in liver cells.

Ketone body production in isolated liver cells and the effect of ketone bodies on hepatocyte urea and glucose production were investigated in acutely uremic rats. Blood beta-hydroxybutyrate levels of starved acutely uremic rats were reduced compared to starved sham-operated controls, suggesting a failure to develop hyperketonemia. On the other hand, beta-hydroxybutyrate concentration is elevated in the liver. Hepatocyte beta-hydroxybutyrate production of acutely uremic animals is enhanced using serine as a substrate. Addition of ketone bodies abolishes this effect. Blood acetoacetate levels of starved acutely uremic rats are elevated compared to sham-operated controls. Liver acetoacetate concentration is unchanged in acute uremia. Hepatocyte acetoacetate production of acutely uremic rats is stimulated using serine and alanine as substrates. Again, this effect is reversed by addition of ketone bodies. Addition of ketone bodies does not affect enhanced glucose production from serine or alanine in hepatocytes of acutely uremic rats but decreases markedly enhanced urea production from serine (156 +/- 35.2 versus 27.4 +/- 7.1) and alanine (80.0 +/- 22.3 versus 42.0 +/- 4.4 nmol mg-1. 30 min-1), especially after bilateral nephrectomy. The data show that the two processes of gluconeogenesis and ureagenesis can be dissociated in hepatocytes of bilaterally nephrectomized rats by the addition of ketone bodies. The finding that ketone bodies decrease the rate of urea production may be worth further study.

Plasma levels of granulocyte lactoferrin, granulocyte myeloperoxidase and granulocyte elastase in complex with alpha 1-proteinase inhibitor (E-alpha 1PI) were investigated in regular hemodialysis patients dialyzed with hollow-fiber dialyzers made from polycarbonate (FD 100) or cuprophan (GFS 120 H). Plasma levels of all these main granulocyte components increased significantly during hemodialysis. E-alpha 1PI levels were significantly higher in patients dialyzed with the polycarbonate compared with the cuprophan membrane, whereas the increases of myeloperoxidase and lactoferrin were not different for the two dialyzers. On the other hand, plasma C3a levels were higher in patients dialyzed with the cuprophan compared with the polycarbonate dialyzer. Therefore, granulocyte activation during hemodialysis does not necessarily need complement activation.

Hepatocytes isolated from the livers of starved, sham-operated, bilaterally nephrectomised and ureter-ligated rats as well as rats with ischaemic acute renal failure were used for a comparative study of the effects of different hormones on gluconeogenesis. In all tested groups dibutyryl-3':5'-adenosine monophosphate inhibits glucose synthesis from pyruvate whereas this process is not affected by glucagon and only slightly activated by adrenalin. In contrast, gluconeogenesis from dihydroxyacetone was stimulated by all three hormones at the expense of the conversion of dihydroxyacetone to lactate. In the presence of l-serine adrenalin, glucagon and dibutyryl cAMP also stimulate glucose synthesis, which is more marked in bilaterally nephrectomised and ureter-ligated animals. In half of the experiments with bilaterally nephrectomised rats (group BN 2), lack of sensitivity of hepatocytes to all tested hormones on gluconeogenesis from serine or dihydroxyacetone was observed. The beta-adrenergic antagonist propranolol reduced the stimulatory effect of adrenalin on glucose synthesis from serine and abolished the influence of catecholamines in the presence of dihydroxyacetone and pyruvate. This suggests that both alpha- and beta-receptors are involved in the activation of hepatic gluconeogenesis. Insulin and parathyroid hormone did not change the rate of glucose synthesis in any of the experimental groups.

Hepatocytes were isolated from rats following bilateral nephrectomy, ureter ligation or sham operation under sodium pentobarbital (Nembutal) anesthesia to investigate the potential role of energy charge and redox state for the gluconeogenetic ability of liver cells. Ketogenesis from l-serine, sodium pyruvate or dihydroxyacetone was significantly higher in hepatocytes of acutely uremic rats indicating higher concentration of reducing equivalents in the mitochondria. During incubation, the mitochondrial redox state characterized by beta-hydroxybutyrate/acetoacetate ratio moved into direction of reduction in all experimental groups, whereas cytosolic redox state characterized by lactate/pyruvate ratio shifted to the oxidative state indicating lack of cytosolic reducing equivalents. Hepatocyte ATP and oxoglutarate production of ureter-ligated rats were significantly higher compared with binephrectomized or sham-operated animals independent of the substrates used. Simultaneously, energy charge showed values higher than 0.85 only in hepatocytes of ureter-ligated animals indicating high energy supply for energy requiring processes. We conclude that hepatic gluconeogenesis and ketogenesis of acutely uremic rats are limited by a lack of cytosolic reducing equivalents independent of cell energy supply.

Plasma levels of granulocyte lactoferrin, granulocyte myeloperoxidase and granulocyte elastase in complex with alpha 1-proteinase inhibitor were investigated during hemodialysis in oliguric patients following cadaveric renal transplantation (CRT). The results were compared with those of patients undergoing regular hemodialysis treatment (RDT) using different membrane materials. In RDT patients, plasma lactoferrin levels increased from 61.9 +/- 10.2 to 417.9 +/- 96.7 using dialyzers made of cuprophane. Dialyzers made of polymethyl methacrylate induced an increase of lactoferrin from 166.6 +/- 28.5 to 712.5 +/- 165.9 and dialyzers made of polyacrylonitrile an increase from 122.6 +/- 23.5 to 647.7 +/- 203.6 ng/ml. In CRT patients, in contrast, plasma lactoferrin levels increased from 49.1 +/- 10.9 to 199.6 +/- 45.9 (cuprophane), from 30.1 +/- 6.9 to 252.5 +/- 46.9 (polymethyl methacrylate), and from 43.3 +/- 9.1 to 174.2 +/- 39.3 ng/ml (polyacrylonitrile). On the other hand, the plasma levels of myeloperoxidase and elastase in complex with alpha 1-proteinase inhibitor increased comparably in both groups of patients. Our data suggest that immunosuppression might prevent degranulation of specific granules independently of the used dialyzer membrane material, whereas no effect was observed on two main components of azurophilic granules.