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Background/aims: The use of antihypertensive medicines has been shown to reduce proteinuria, morbidity, and mortality in patients with chronic kidney disease (CKD). A specific recommendation for a class of antihypertensive drugs is not available in this population, despite the pharmacodynamic differences. We have therefore analysed the association between antihypertensive medicines and survival of patients with chronic kidney disease., Methods: Out of 2687 consecutive patients undergoing kidney biopsy a cohort of 606 subjects with retrievable medical therapy was included into the analysis. Kidney function was assessed by glomerular filtration rate (GFR) estimation at the time point of kidney biopsy. Main outcome variable was death., Results: Overall 114 (18.7%) patients died. In univariate regression analysis the use of alpha-blockers and calcium channel antagonists, progression of disease, diabetes mellitus (DM) type 1 and 2, arterial hypertension, coronary heart disease, peripheral vascular disease, male sex and age were associated with mortality (all p<0.05). In a multivariate Cox regression model the use of calcium channel blockers (HR 1.89), age (HR 1.04), DM type 1 (HR 8.43) and DM type 2 (HR 2.17) and chronic obstructive pulmonary disease (HR 1.66) were associated with mortality (all p < 0.05)., Conclusion: The use of calcium channel blockers but not of other antihypertensive medicines is associated with mortality in primarily GN patients with CKD., (© 2015 S. Karger AG, Basel.)

Predialysis volume overload is the sum of interdialytic weight gain (IDWG) and residual postdialysis volume overload. It results mostly from failure to achieve an adequate volume status at the end of the dialysis session. Recent developments in bioimpedance spectroscopy and possibly relative plasma volume monitoring permit noninvasive volume status assessment in hemodialysis patients. A large proportion of patients have previously been shown to be chronically volume overloaded predialysis (defined as >15% above 'normal' extracellular fluid volume, equivalent to >2.5 liters on average), and to exhibit a more than twofold increased mortality risk. By contrast, the magnitude of the mortality risk associated with IDWG is much smaller and only evident with very large weight gains. Here we review the available evidence on volume overload and IDWG, and question the use of IDWG as an indicator of 'nonadherence' by describing its association with postdialysis volume depletion. We also demonstrate the relationship between IDWG, volume overload and predialysis serum sodium concentration, and comment on salt intake. Discriminating between volume overload and IDWG will likely lead to a more appropriate management of fluid withdrawal during dialysis. Consensually, the present authors agree that this discrimination should be among the primary goals for dialysis caretakers today. In consequence, we recommend objective measures of volume status beyond mere evaluations of IDWG., (Copyright © 2013 S. Karger AG, Basel.)

Background: Treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin 2 receptor blockers (ARBs) is associated with an increased risk for acute kidney injury after cardiovascular interventions. However, for patients undergoing kidney biopsy, no data is available., Methods: Four hundred and sixty-six patients undergoing kidney biopsy were retrospectively analyzed of whether or not concomitant intake of ACEIs or ARBs impairs kidney function., Results: Three hundred and twenty-three patients received ACEIs or ARBs or both before kidney biopsy. ACEI/ARB intake had no effect on kidney function compared to patients without this medication (all p > 0.05)., Conclusion: Treatment with ACEIs or ARBs is not associated with risk of acute kidney injury in subjects undergoing kidney biopsy., (Copyright © 2012 S. Karger AG, Basel.)

Background/aims: In hemodialysis and hemodiafiltration patients, the plasma sodium (PNa) measured before dialysis can be regarded as the sodium setpoint. By the end of dialysis, the PNa typically approximates the prescribed dialysate sodium (DNa), the difference between DNa and PNa being considered the sodium gradient. We determined the relationship between setpoint, gradient and pre- to postdialysis PNa change (delta PNa), and studied associations with dialysis-related variables., Methods: Cohort study. Measurements from 132 patients during 12 consecutive treatments included PNa and DNa concentrations, pre- to postdialysis body weight and predialysis systolic blood pressure., Results: Sodium setpoints were normally distributed (137.9 ± 2.4 mmol/l), DNa prescriptions were non-normally distributed (138.9 ± 1.8 mmol/l). The sodium gradient correlated strongly with delta PNa (r = 0.76, p < 0.001). Both sodium gradient and delta PNa correlated with relative interdialytic weight gain (IDWG; r = 0.25, p = 0.004, and r = 0.44, p < 0.001, respectively), but not with predialysis systolic blood pressure. These correlations were consistent after exclusion of patients with urine volume >500 ml/day and patients undergoing sodium profiling, and increased after exclusion of patients with hemodiafiltration protocols. Predictors for having higher relative IDWG (≥2.8%) were delta PNa concentrations ≥0 mmol/l and younger age. Predictors for having a delta PNa concentration ≥0 mmol/l were lower sodium setpoints, higher DNa prescriptions, use of Nikkiso machines, sodium profiling and younger age. Patients with positive delta PNa despite negative gradients were significantly younger, used more Nikkiso machines and presented with higher IDWG., Conclusion: IDWG correlated with the sodium gradient and more strongly with delta PNa, suggesting the need for studying other outcomes, such as morbidity and mortality., (Copyright © 2010 S. Karger AG, Basel.)

Background: The effect of serum prolactin levels on the response to erythropoiesis-stimulating agents (ESA) in patients on chronic hemodialysis is unknown., Methods: We included 111 stable hemodialysis patients in this study and examined the association of serum prolactin concentrations with the response to ESA. Accordingly we implemented an ESA index as a measure of therapeutic efficacy. The two outcomes of this cohort study were the association of prolactin concentrations with response to ESA, both at baseline (cross-sectional component) and after 1-year of follow-up (prospective component), and the presence of macroprolactin., Results: Two male patients, but none of the female patients, had serum prolactin concentrations within the reference range. Following precipitation with polyethylene glycol (PEG), 17 males (25.4%) and 9 females (20.6%) had serum prolactin concentrations within the reference range. Females had somewhat higher levels than males: 39.8 (IQR 32.3-64.5) versus 27.8 (IQR 23.4-47.8) ng/ml (p = 0.003). The ratio of prolactin(PEG)/prolactin(Native) was greater than 0.60 in 103 patients (92.8%), thus excluding significant amounts of macroprolactin. From uni- and multivariate analyses we did not find associations of serum prolactin concentrations with a response to ESA either at baseline or at follow-up., Conclusions: From this prospective study we provide evidence that elevated serum prolactin levels are not related to the presence of macroprolactin in chronic hemodialysis patients. Furthermore, serum prolactin concentrations are not associated with the response to erythropoietic therapy in these individuals., (Copyright 2007 S. Karger AG, Basel.)

Increments of oxidative stress have been addressed as one potential cause for the accelerated atherosclerosis of chronic kidney disease patients. Ascorbate represents one of the most prominent antioxidants both in plasma as well as intracellulary, exerting beneficial effects by an inhibition of lipid peroxidation and by reducing endothelial dysfunction. However, in the presence of transition metals like iron, ascorbate may give rise to an increased generation of oxidants, and ascorbylation may impose additional carbonyl stress to uremic patients. Unsupplemented dialysis patients have reportedly lower plasma levels of ascorbate in comparison to healthy controls, mostly due to a loss into the dialysate or, in case of not dialyzed patients, increased urinary losses. Currently, 60 mg of ascorbate are recommended for chronic kidney disease patients, and 1-1.5 g of oral ascorbate/week in case of suspected subclinical ascorbate deficiency or 300 mg parenteral ascorbate/dialysis session, respectively. Ascorbate's role in modifying arterial blood pressure remains unclear, but anemic patients with functional iron deficiency might benefit from short-term, moderately dosed ascorbate supplements., (Copyright 2003 S. Karger AG, Basel)

Degranulation of polymorphonuclear leukocytes (PMNL) occurs during extracorporeal circulation. A degranulation-inhibiting protein identical to angiogenin was recently isolated from high-flux dialyzer ultrafiltrate. This protein inhibits the release of lactoferrin and metalloproteinases from PMNL in vitro. In the present study, we investigated end-stage renal disease patients undergoing regular hemodialysis treatment with either high-flux dialyzers (n = 51) or low-flux dialyzers (n = 44), and chronically uremic patients undergoing hemodiafiltration (n = 30). Hemodialysis therapy with low-flux polysulfone or cellulose triacetate membranes caused no or only minimal reduction (

Oxidative stress contributes to the pathophysiology of kidney injury. Beneficial renal effects of some medications, such as angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor antagonists, calcium channel blockers, beta-blockers and lipid lowering agents depend at least partially on the ability to alleviate oxidative stress. The administration of various natural or synthetic antioxidants has been shown to be of benefit in prevention and attenuation of renal scaring in numerous animal models of kidney diseases. These include vitamins, N-acetylcysteine, alpha-lipoic acid, melatonin, dietary flavonoids and phytoestrogens, and many others. Human studies are limited in this regard. Under certain conditions, surprisingly, the antioxidant supplements may exhibit pro-oxidant properties and even worsen renal damage. To date, the evidence is insufficient to recommend antioxidant supplements in patients with kidney disease. Prospective, controlled clinical trials on safety and effectiveness of different therapeutic antioxidant strategies are indispensable., (Copyright 2003 S. Karger AG, Basel)

Background/aims: Growth hormone (GH) resistance leads to enhanced protein catabolism and contributes to the malnutrition of patients with chronic renal failure (CRF). In short-term trials anabolic effects of rhGH therapy have been demonstrated in patients on chronic hemodialysis., Methods: This study was initiated to determine the effects of 12 months of rhGH therapy on polymorphonuclear leukocyte (PMNL) function as well as on nutritional and anthropometric parameters. 0.125 IU/kg rhGH was given 3 times a week during the first 4 weeks and 0.25 IU/kg thereafter to 19 malnourished hemodialysis patients with a mean age of 59.3 +/- 13.4 years., Results: Insulin-like growth factor I (IGF-I) concentrations rose significantly from 169.2 +/- 95.6 to 262.9 +/- 144.4 ng/ml (p < 0.01) in the first 3 months, but declined thereafter. Phagocytic activity of PMNLs also increased significantly in response to rhGH therapy and this activation remained stable over the whole 12-month period. Other parameters of PMNL function were not influenced by rhGH therapy. In addition, nutritional parameters such as albumin, prealbumin, transferrin, cholesterol, HDL-cholesterol, cholinesterase, predialytic creatinine and blood urea nitrogen were not affected by rhGH therapy. A decline of total body fat (TBF) was observed after 3 and 9 months of rhGH therapy (17.5 +/- 10 vs. 16.7 +/- 10% after 3 months, p < 0.017 and 16.8 +/- 8.7% after 9 months, p < 0.049), whereas lean body mass remained stable., Conclusions: Twelve months of rhGH therapy caused a significant increase in IGF-I levels, stimulated phagocytic activity of PMNLs and induced a decline of TBF. Other anthropometric and nutritional parameters were not affected, which might be related to the persistence of GH resistance., (Copyright 2003 S. Karger AG, Basel)

The high mortality rate seen in dialysis patients is related to long-standing high blood pressure and the presence of other traditional as well as non-traditional risk factors for cardiovascular disease. Hypertension is associated with increased risk for left ventricular hypertrophy, coronary artery disease, congestive heart failure and cerebrovascular complications. High blood pressure is frequent and difficult to control in the dialysis population. Available therapeutic options to normalize blood pressure in these patients include dietary salt and fluid restriction in combination with reduction of dialysate sodium concentration. A possible treatment option for these patients may be long, slow hemodialysis (3 x 8 h per week); short daily hemodialysis (2-3 h 7 times per week); nocturnal hemodialysis (6-7 times overnight per week). Reduction of residual renal function is a major cause of blood pressure increase in the peritoneal dialysis patient population. Therefore, hyperhydration should be avoided. If antihypertensive medication is needed, ACE inhibitors, beta-blockers and/or calcium channel blockers are recommended. Optimal blood pressure in dialysis patients is not different from recommendations for the general population., (Copyright 2003 S. Karger AG, Basel)

Effective erythropoiesis requires both erythropoietin and iron. Regular, intravenous iron supplements represent a standard adjuvant therapy for the treatment of anemia of chronic kidney disease. In this paper, the authors speculate upon potential deleterious effects of intravenous iron on cellular physiology in the setting of the increased oxidant burden of hemodialysis patients., (Copyright 2002 S. Karger AG, Basel)

Essential hypertension causes renal injury. Hypertensive nephroangiosclerosis (HN) or hypertensive nephropathy are terms most commonly used to describe this renal pathology. Although specific histological lesions occurring in affected kidneys are well known, pathogenesis of hypertension-related renal scarring is not completely understood. Evidence exists to support the theory that other factors such as aging, black race or smoking, beside blood pressure, contribute to the development and progression of HN. Metabolic disturbances, cocaine and nonsteroidal anti-inflammatory drug abuse, ochratoxin A exposure, dietary salt intake, heavy metal toxicity, hantavirus infection and perinatal programming are also considered risk factors. Renal susceptibility genes may determine whether hypertension-induced progressive renal damage occurs and how severe it is. Determination of all risk factors may identify patients at high risk of renal failure and help tailor an appropriate management. In the present paper, the knowledge available on this clinically important objective is discussed., (Copyright 2002 S. Karger AG, Basel)

Background: During pregnancy, familial hyperlipidemia or systemic lupus erythematosus (SLE) can exacerbate having devastating consequences for both mother and fetus. Immunoadsorption is established for removal of pathogenic proteins lipoproteins or autoantibodies, but this procedure has only rarely been used in pregnancy., Methods: We evaluated retrospectively 126 extracorporeal treatments during six pregnancies. Forty low-density lipoprotein immunoadsorptions, 6 sole plasma exchanges and 36 combined procedures (plasma exchange followed by immunoadsorption) were performed for severe hypertriglyceridemia, complicated by acute pancreatitis. Forty-four IgG immunoadsorptions were executed in 2 pregnant women suffering from SLE with a disastrous course during prior pregnancies., Results: In hyperlipidemic pregnant women, mean triglyceride levels prior to treatment were 3,841 +/- 2,076 mg/dl (mean +/- SD) and total cholesterol was 617 +/- 354 mg/dl. Until delivery, a 27% reduction of triglycerides could be achieved. Clinical and serological signs of pancreatitis disappeared after initiation of extracorporeal therapy. Four healthy babies were delivered (birthweights between 2,250 and 3,360 g). In 1 woman suffering from SLE, intrauterine fetal death occurred in the 22nd week of gestation despite a reduction of cardiolipin antibodies by 69%. The second case (a twin pregnancy) was complicated by steroid-resistant antibody-mediated anemia. Due to frequent immunoadsorptions, red blood cell count improved (reduction of antierythrocyte antibodies by 66.6%) and 2 healthy babies (birthweights 2,120 and 2,350 g) were delivered by cesarean section., Conclusion: Long-term antibody-based immunoadsorption has been demonstrated to be safe and well tolerated in pregnant women and enables normal intrauterine/fetal development. Although rarely indicated during pregnancy, this treatment modality might be a promising new technique for removal of autoantibodies and lipoproteins in patients with serious gestational complications without sufficient response to conventional therapy., (Copyright 2002 S. Karger AG, Basel)

Background: Mutations in the carboxy termini of the beta subunit (hbetaENaC) and the gamma subunit (hgammaENaC) of the human epithelial sodium channel have been identified in patients with Liddle syndrome. Moreover polymorphisms have been described in these genes, the clinical relevance of which for progression to end-stage renal disease (ESRD) is unknown. We, therefore, have screened ESRD patients for putative variants of these genes., Methods: We investigated 256 chronic hemodialysis patients, including 123 patients with a history of hypertension as a cause of ESRD. Screening for mutations in the carboxy termini of hbetaENaC and hgammaENaC was accomplished by polymerase chain reaction amplification followed by single-strand conformation polymorphism analysis., Results: In 231 patients single-strand conformation polymorphism analysis of the polymerase chain reaction fragments of the hbetaENaC and hgammaENaC genes showed a similar migration pattern as compared with negative control subjects. In 25 patients a band shift was observed. However, sequence analysis in all these patients revealed wild-type sequence., Conclusions: The present study demonstrates the absence of genetic variants in the carboxy terminus of the hbetaENaC and hgammaENaC genes in Austrian patients with ESRD maintained on chronic hemodialysis treatment. Thus, mutations in these genes are unlikely to be associated with ESRD.

Oral intake of freshly voided morning urine has been recommended for many diseases such as viral or bacterial infections. Symptoms reported during the first days of oral intake of urine include nausea, vomiting, headache, palpitations, diarrhea or fever. Several substances in the urine are believed to be important for oral intake such as urea, uric acid, cytokines, hormones or urokinase. Local urine therapies include embrocations, compresses for local tumors, whole body bath or foot bath in the urine, use of urine as eye drops, ear drops or nose drops and the use of urine for wound cleaning.

Objective: Systematic investigations on the status of fat-soluble vitamins in patients with acute renal failure (ARF) are lacking and hence no recommendations for vitamin supply can be defined for these subjects. Thus we compared the status of fat-soluble vitamins, of transport molecules and some vitamin-dependent proteins in patients with ARF and healthy controls., Setting: Nephrology unit of a university hospital., Patients and Methods: Eight patients with ARF requiring hemodialysis therapy were investigated and 28 healthy volunteers served as controls. Plasma concentrations of retinol (vitamin A) and retinol-binding protein (RBP), 25-OH and 1,25-(OH)2 vitamin D3, of parathyroid hormone (PTH), of alpha-tocopherol (vitamin E) and of phylloquinone (vitamin K), osteocalcin and noncarboxylated osteocalcin, respectively, were measured and plasma lipoprotein fractions (as vitamin transport vehicle) were evaluated., Results: Vitamin A levels were decreased (p < 0.001), but RBP levels were normal in ARF patients. Vitamin D3 metabolites 25-OH and 1,25-(OH)2 vitamin D3 plasma levels were profoundly depressed, and PTH was elevated (p < 0.001). Vitamin E plasma concentration was reduced (p < 0.001) but this cannot be accounted for by decreased LDL cholesterol or triglyceride levels. In contrast, vitamin K plasma level was rather elevated in ARF patients with a broad range of individual values. Blood coagulation was normal but total and carboxylated osteocalcin were decreased. No correlation of vitamin K concentrations and any of the plasma lipoprotein fractions could be identified., Conclusion: With the exception of vitamin K, profound deficiencies of fat-soluble vitamins develop in patients with ARF. Current recommendations for vitamin supplementation are inadequate and should be reevaluated for these patients.

Susceptibility to bacterial infections in the peritoneal cavity is a serious problem for peritoneal dialysis patients. Uremic toxins are among the causes of the diminished function of polymorphonuclear leuckocytes (PMNLs), cells of the local immune defense. We isolated from the peritoneal dialysis effluent of a uremic patient, a peptide that inhibits PMNL chemotaxis in a concentration-dependent manner. The amino terminus of this factor is identical to that of ubiquitin. The peptide shows the same size as ubiquitin on SDS-polyacrylamide gels, but has a more acidic isoelectric point than intact ubiquitin, which has no effect on PMNL chemotaxis. We conclude that we have isolated a modified form of ubiquitin and that this modification is responsible for its inhibiting effect on PMNL chemotaxis.

There is no doubt that acute renal failure (ARF) is associated with enhanced protein breakdown. It has been shown that protein split products can be measured in plasma samples of these patients. On the other hand, ARF frequently occurs in conditions of increased metabolic stress which leads to enhanced protein catabolism. Muscle wasting, loss of lean body weight, and a negative nitrogen balance result in malnutrition which considerably increases morbidity and mortality. Besides the accumulation of uremic toxins, several other factors are involved in the accelerated proteolysis in ARF. Metabolic acidosis appears to be one of the major catabolic factors in chronic renal failure, and probably in ARF as well. Insulin resistance, which is commonly attributed to uremia, also increases protein degradation. However, this derangement of carbohydrate metabolism is not directly accessible to therapy, in contrast to acidosis, which can be easily corrected by bicarbonate administration. There is further evidence that glucocorticoid excess contributes to the enhanced muscle proteolysis in ARF. Moreover, several studies have demonstrated that only in the presence of both glucocorticoids and acidosis could proteolysis occur. Investigation of the cellular mechanism by which muscle proteins are degraded indicates the importance of the cytosolic, soluble ATP- and ubiquitin-dependent proteolytic system. Successful treatment of various catabolic conditions with recombinant human growth hormone and insulin-like growth factor-I seems to be a promising strategy in severely catabolic patients with ARF. Anticytokine therapy appears to be another promising treatment in the course of catabolic illness due to sepsis; however, clinical application is still in its infancy.

Patients undergoing regular hemodialysis treatment display elevated intracellular free calcium and impaired glucose uptake in polymorphonuclear leukocytes (PMNLs) in the presence of enhanced serum parathyroid hormone (PTH) levels. Normalization of intracellular calcium can be achieved by different therapeutic interventions acting by different mechanisms. Effective oral 1,25-dihydroxyvitamin D3 therapy (0.5-1.0 microgram/day) normalizes PMNL cytosolic calcium via suppression of PTH levels. Hemodialysis patients treated orally with the calcium channel blocker nitrendipine (20-40 mg/day) normalizes calcium without affecting serum PTH levels. Both therapeutic interventions improved glucose uptake and displayed no synergistic effect.

Hemodialysis (HD) leads to neutrophil activation depending on the membrane material used. Calcium plays a major role in PMN function and metabolism. A rise of cytosolic free calcium [Ca2+]i is an important intracellular messenger for neutrophils. In this study we measured intracellular resting Ca2+ and the chemotactic peptide FMLP-stimulated intracellular Ca2+ during HD using membranes made of polysulfone and polymethylmethacrylate (PMMA). Also, we investigated the effect of continuous infusion of nifedipine in a dose of 18 micrograms/kg/h during HD with PMMA. Only HD with PMMA causes an increase of both resting and FMLP-stimulated [Ca2+]i after 30 min of starting HD. Polysulfone did not affect [Ca2+]i. Continuous infusion of nifedipine during HD with PMMA completely inhibited these changes of [Ca2+]i. Although the existence of voltage-sensitive calcium channels has not been proved, the present data provide further indirect evidence either for the existence of calcium channels or for a mechanism of action that is independent of antagonism.

There is a high incidence of infection in hospitalized patients with chronic renal failure. Nutritional and metabolic factors, as well as vitamins and trace elements are involved in impaired host defence and altered PMN function in dialysis patients. A circulating peptide (GIP) could be isolated from uremic serum that inhibits PMN glucose uptake, chemotaxis, oxidative metabolism and intracellular killing of Staphylococcus aureus. In addition to enhanced susceptibility to infection by impaired PMN function, uremic patients show profound defects of specific immune system represented by monocytes, B cells and T cells. T cells show decreased proliferation and Il-2 production on the one hand and enhanced Il-2 receptor expression on the other. Monocytes fail to elicit adequate help for T cell proliferation despite normal production of Il-1 and Il-6, but they produce elevated amounts of TNF alpha. B cells secrete decreased amounts of IgG and respond insufficiently to various vaccines. Malnutrition and uremia induce severe alterations of host defence and specific immune system if a combination of both these diseases occur.

Recombinant human erythropoietin (r-HuEPO) represents the therapy of choice in anaemia of chronic renal failure. A number of studies have analysed the relative effectiveness of r-HuEPO administered subcutaneously (s.c.) or intravenously (i.v.) in haemodialysis patients. The bioavailability of s.c. r-HuEPO appears to be low and the absorption of r-HuEPO variable. Nevertheless, s.c. administration of r-HuEPO is more efficacious than i.v. administration, probably due to the better time-averaged plasma concentrations. Patients on haemodialysis who were on i.v. r-HuEPO 3 times weekly for 9 months were subsequently successfully maintained on a self-administered s.c. dosage which was 50% of the i.v. maintenance dosage and which was later reduced further to 30% of the weekly i.v. maintenance dosage. An ongoing European multicentre study has confirmed these findings and demonstrated that s.c. administration 3 times weekly and once daily was as effective as i.v. administration 3 times weekly. Both these s.c. regimens resulted in a significant dosage reduction (30%) compared with the i.v. regimen. The study also found that once weekly s.c. dosing was as effective as 3 times weekly i.v. dosing but did not result in a dosage reduction. Other studies on the optimization of s.c. r-HuEPO in patients on continuous ambulatory peritoneal dialysis demonstrated that haemoglobin levels following s.c. r-HuEPO administration (60 U/kg twice weekly) can be further increased by 2 ml iron dextran (containing 50 mg/ml iron) administered i.v. 7-9 weeks after the start of therapy. Studies on the site of s.c. injection reveal that injection into the thigh results in more rapid absorption, higher peak concentrations and greater bioavailability than injection into the arm or abdomen. Data also demonstrate the economic advantage of s.c. r-HuEPO in high-risk patients.

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.

Dyslipidemia of chronic renal failure is of multifactorial origin. Decreased activity of lipoprotein lipase and hepatic triglyceride lipase, peripheral insulin resistance, hyperparathyroidism and L-carnitine deficiency are the contributing factors. This results in a disturbed catabolism of chylomicron, accumulation of very-low-density (VLDL) and intermediate-density (IDL) lipoproteins as well as incompletely cleared remnant particles, whereas low-density lipoprotein (LDL) levels are diminished. There is current debate as to whether cardiovascular disease is accelerated and whether hyperlipidemia should specifically be treated. In addition, there have been few means of influencing these metabolic alterations. Drug incompatibility and consequently side effects render treatment difficult. The drugs that have been most tested for lipid lowering in chronic renal failure are the fibric acids. By their mode of action, they are the logical choice. Dose reduction overcomes major side effects such as myopathy and rhabdomyolysis. The second generation of fibric acid derivatives (gemfibrozil and beclobrate) show several advantages over formerly used derivatives. Treatment with lovastatin and simvastatin appears to be safe and is recommended in a minority of patients with predominantly elevations of LDL. HMG-CoA reductase inhibitors also lower remnant particles effectively in hemodialysis (HD) patients. L-Carnitine and low-molecular-weight heparin have been shown to influence VLDL rich in triglycerides in a subset of patients on HD. In posttransplant hyperlipidemia, diet remains the first course of action in all patients. When this approach fails, the new lipid-lowering agents, especially fibric acids, appear to be safe in short-term studies in azathioprine- and ciclosporin-treated patients. Lovastatin has been shown to be safe in stable renal transplant patients. Its toxicity seems to depend mainly on high ciclosporin whole blood through or plasma levels.

Membrane plasma separation uses artificial polymers which might interact with blood components during treatment. In 7 patients treated for familial hypercholesterolemia with heparin-induced extracorporeal LDL precipitation (HELP), we studied 4 different synthetic plasma separation materials. The effect of membranes made from polyethylene, polymethylmethacrylate (PMMA), polypropylene and polysulfone on complement activation (C3a), granulocyte elastase release and granulocyte count were measured repeatedly during the treatment. Polyethylene and PMMA induced high levels of plasma elastase and marked granulocytopenia after 60 min of treatment, much later than during hemodialysis, where granulocyte nadir is known to occur already after 15 min. Polysulfone and polypropylene did not change granulocyte counts and caused only modest levels of elastase during plasmapheresis. Complement activation was present in all 4 membranes but with polyethylene, very high concentrations of C3a were detected. These data indicate that irritation of immune system components as granulocytes or the complement system do occur during plasmapheresis to different degrees depending on the membrane material used. Reinfusion of plasma after processing increases the amount of plasmatic activation products infused into the patient. This was the case, although the plasma processing procedure itself did not add activation products to the plasma. Activation patterns during plasma separation differ from those known to occur during hemodialysis despite use of the same polymer. Immunocompromised patients treated with plasmapheresis may react differently than these otherwise healthy subjects with familial hypercholesterolemia.

Serum magnesium as well as total and fractional urinary magnesium excretion were investigated in 87 renal transplant recipients under immunosuppression with azathioprine/prednisone (n = 18), ciclosporin/prednisone (n = 33) or ciclosporin/azathioprine/prednisone (n = 36). Only patients treated with ciclosporin and prednisone displayed significantly lower serum magnesium (1.8 +/- 0.03 mg/dl), compared to azathioprine-treated ones (2.0 +/- 0.07 mg/dl; p less than 0.05). Mean serum magnesium values of all three groups remained in the lower normal range (1.7-2.7 mg/dl). Fractional but not total magnesium excretion was significantly (p less than 0.05) higher in both ciclosporin-treated groups (5.8 +/- 0.38 and 5.6 +/- 0.40%) compared to patients on azathioprine (4.5 +/- 0.48%). None of the patients developed clinical signs of hypomagnesemia and only 7 patients were on oral supplementation with magnesium containing antacida. Our study did not confirm earlier observations of severe magnesium wasting and hypomagnesemia in renal transplant recipients under immunosuppression with ciclosporin.

Complement activation occurs during hemodialysis, and its intensity depends on the type of dialyzer and whether it is new or reused. Neutrophil degranulation also occurs during hemodialysis with release of lactoferrin, myeloperoxidase and elastase. However, it is unclear whether this event is induced by complement activation and whether it is attenuated by reuse. We examined complement activation and neutrophil degranulation during 10 consecutive hemodialyses using the same cuprophane dialyzer. Also the effect of rinsing the latter with 25% human albumin was studied. The rise in plasma C3a and C5a was markedly higher (p less than 0.01) during the first than the second use. Plasma levels of lactoferrin and myeloperoxidase increased significantly (p less than 0.01) during the first use, and levels were not affected by reuse. In contrast, plasma elastase increased with the first use and decreased with each subsequent use. Treatment of the dialyzer with albumin did not affect the magnitude of rise in plasma levels of C3a or lactoferrin but was associated with a significant reduction in plasma elastase. The data show that neutrophil degranulation is not dependent on complement activation and that the two processes could be dissociated.

Carbohydrate metabolism in salivary glands of acutely uremic rats was investigated. In the submandibular glands there was an increase of total carbohydrate and glycogen content 24 and 48 h following binephrectomy or ureter ligation. In contrast, lactate concentration was significantly lower. Similar alterations of carbohydrate metabolism could not be observed in sublingual or parotid glands of acutely uremic rats.

The potential role of the kidney in renal serine synthesis was elucidated in rats following dietary serine as well as serine and glycine depletion for 6 weeks. Serine deficient diet caused a significant rise in blood serine and glycine values. In contrast, blood glycine concentration decreased significantly following serine and glycine depletion, whereas blood serine levels remained unchanged. Bilateral nephrectomy caused a significant decrease of blood serine values of control and serine deficient rats. Serine concentration, however, was not affected by bilateral nephrectomy following serine and glycine deficiency indicating kidney-independent serine synthesis under these conditions. There was a significant increase of blood lactate and pyruvate levels under serine and serine/glycine deficient diet compared with control animals, whereas blood ketone bodies fell. In contrast, 24 h after bilateral nephrectomy blood ketone bodies rose and blood lactate and pyruvate concentrations decreased significantly. 24 h after bilateral nephrectomy there was a marked rise in blood citrate values of female rats compared with male animals indicating sex dependency of kidney citrate metabolism in the rat.

Neutral proteinases of neutrophilic polymorphonuclear leukocytes were followed up cytochemically in blood smears of 12 patients submitted to regular hemodialysis treatment (RDT). Halo formation (ring-shaped area around each neutrophil due to protein degradation) was reduced in all patients with end-stage renal disease under RDT. Concomitant to the development of leukopenia, a maximal increase of the plasma levels of the granulocytic elastase in complex with alpha 1-proteinase inhibitor was observed 3 h after starting hemodialysis (+409%; p less than 0.001). On the other hand, the proteolytic activity of the plasma samples against azocasein as substrate, being significantly higher (+244%; p less than 0.001) in RDT patients compared with healthy controls, decreased permanently during therapy (-71%; p less than 0.001; 3 h after initiation of the treatment). The mechanisms of release as well as of elimination of proteolytic activity due to RDT are discussed.

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.

Isolated hindquarters of bilaterally nephrectomized and sham-operated rats were perfused in the presence and absence of 14C-labelled serine, respectively. After a perfusion period of 30 min 14C-serine was 4,074 +/- 270 dpm/ml in the perfusion medium of sham-operated animals and decreased to 2,800 +/- 190 dpm/ml in the medium of acutely uraemic rats. Muscle glycogen concentration in sham-operated animals was 1.10 +/- 0.04 mg/g wet weight in the absence and 1.03 +/- 0.11 mg/g in the presence of serine. In contrast, in acutely uraemic rats there was a glycogen concentration of 0.57 +/- 0.09 mg/g in the absence of serine. Glycogen was increased in the presence of serine in the perfusion medium, the value being 1.50 +/- 0.13 mg glycogen/g wet weight. Incorporation of labelled serine into skeletal muscle glycogen was significantly higher in acutely uraemic animals (15 +/- 0.5 mumol/g glycogen) than in sham-operated animals (10 +/- 0.4 mumol/g). The results are compatible with the hypothesis that serine increases muscle glycogen synthesis in acute uraemia.

Glycogen content as well as the enzymes of glycogenolysis and glycogen synthesis were examined in myocardium, skeletal muscle, liver and kidneys of rats with dietary phosphorus deprivation. Myocardial glycogen content was decreased and this was accompanied by activation of the enzymes of glycogenolysis and inhibition of the enzymes of glycogen synthesis. Beta blockade (nadolol) abolished the effect of phosphorus depletion (PD) on myocardial glycogen metabolism, documenting that the effect of PD is mediated, at least in part, by increased sympathetic activity. Furthermore, administration of insulin caused a marked increase of glycogen content in the heart of both control and phosphorus-depleted (PD) animals. There was no change of glycogen content or the activities of enzymes of glycogen metabolism in skeletal muscle or kidney, but a decrease of glycogen content of the liver was observed in PD animals.

Rapid proteolytic digestion of three subunits of phosphorylase kinase was shown in plasma ultrafiltrates from a patient who was admitted with multiple traumatic injuries, respiratory insufficiency, hemorrhagic shock and acute renal failure. The observed cleavage of phosphorylase kinase may be a consequence of protease-antiprotease imbalance. After an initial determination of 80 mg/dl the alpha 2-macroglobulin values were too low to be detected. Addition of purified alpha 2-macroglobulin to the ultrafiltrates resulted in complete inhibition of phosphorylase kinase digestion in vitro. Aprotinin did not inhibit proteolytic digestion. Daily dialysis did not ameliorate the observed protein catabolism of this patient. These findings may have clinical application in hypercatabolic states, if alpha 2-macroglobulin becomes available in a form suitable for human use.

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.