Search

Background Contrast-associated acute kidney injury (CA-AKI) is a potential risk associated with the percutaneous coronary interventions (PCI) for chronic total coronary occlusions (CTO). This study should evaluate the incidence of CA-AKI in an era of advanced strategies of recanalization techniques and identify modifiable determinants. Methods We analysed 1924 consecutive CTO procedures in 1815 patients between 2012 and 2019. All patients were carefully monitored at least up to 48 h after a CTO procedure for changes in renal function. Results The incidence of CA-AKI was 5.6%, but there was no relation to the technical approach such as frequency of the retrograde technique, intravascular ultrasound or radial access. Procedures with CA-AKI had longer fluoroscopy times (37.6 vs 46.1 min; p = 0.005). The major determinants of CA-AKI were age, presence of diabetes and reduced ejection fraction, as well as chronic kidney disease stage ≥2, serum haemoglobin, and fluoroscopy time. Contrast volume or contrast volume/GFR ratio were not independent determinants of CA-AKI. Periprocedural perforations were more frequent in CA-AKI patients (11.3 vs 2.3%; p Conclusions CA-AKI was associated with the risk of in-hospital adverse events. Established patient-related risk factors for CA-AKI (age, diabetes, preexisting chronic kidney disease, low ejection fraction) were confirmed in this study. In addition, the length of the procedure, coronary perforations and low preprocedural serum haemoglobin were risk factors that might be preventable in patients at high risk for CA-AKI.

Was ist neu? Steroidfreie Immunsuppression Der Verzicht auf Steroide nach Nierentransplantation kann einen Diabetes mellitus verhindern, ohne dass ein gehäuftes Auftreten von akuten Abstoßungen bei Patienten mit niedrigem immunologischem Risiko beobachtet werden konnte. Risiken der Lebendspende Die Lebendnierenspende ist eine wichtige Alternative zur postmortalen Nierenspende, allerdings bestehen perioperative und längerfristige Risiken für den Spender. Patienteninformation bei Dialyse Seit Jahren ist bekannt, dass die Wahl eines Nierenersatzverfahrens am besten in einem Prozess der partizipativen Entscheidungsfindung (shared decision making) erreicht wird. Nun liegt eine kontrollierte Studie (CORETH-Projekt, Halle) vor. Die Zufriedenheit mit der Verfahrenswahl hängt vom Grad der Information ab; Patientenschulungen wie das Nierenstark-Training der Deutschen Nierenstiftung können eingesetzt werden. Dialysezugang Der Dialysezugang, Peritonealdialysekatheter und insbesondere der Hämodialyse-Shunt sind mittlerweile als Verfahren standardisiert und weiterentwickelt worden. Das neu-aufgelegte deutschlandweite interdisziplinäre Zertifizierungsverfahren von Shuntzentren bietet weitere qualitative Entwicklungsmöglichkeiten und Expertise. Dialysattemperatur Die Dialysattemperatur kann zur Kreislaufstabilisierung reduziert werden. In der „slow extended“-Form der Dialysebehandlung ist diese Maßnahme gut etabliert. In der intermittierenden Dialysebehandlung muss auf Nebenwirkungen geachtet werden und zugunsten des gewünschten Effektes abgewogen werden. Der Effekt auf die Dialyseeffizienz ist bislang unklar.

Peritonealdialyse und Herzinsuffizienz Peritonealdialyse (PD) bei Herzinsuffizienz fuhrt zu einer signifikanten Abnahme des Korpergewichts, zu einer signifikanten Verbesserung des NYHA-Stadiums und zu einer deutlich geringeren Hospitalisationsrate. Die Diuretikadosis, die linksventrikulare Funktion und die GFR sind durch die PD nicht signifikant verandert. Icodextrin und Insulinresistenz Die Insulinresistenz wird durch Icodextrin im Vergleich zu den konventionellen glukosehaltigen Losungen der PD verbessert, insbesondere bei Diabetikern. Auch Stoffwechselgesunde profitieren davon. Aldosteron-Antagonisten bei Dialysepatienten Aldosteronantagonisten sind bei Dialysepatienten mit Herzinsuffizienz vorteilhaft. Das Risiko einer Hyperkaliamie scheint jedoch auch bei diesen Patienten bedeutsam. Magnesiumspiegel als Risikofaktor Magnesiummangel ist mit einer hoheren Mortalitat verknupft. Diese Assoziation ist insbesondere dann bedeutsam, wenn ein Albuminmangel vorliegt. Asymptomatische Bakteriurie nach Nierentransplantation Die asysmptomatische Bakteriurie stellt ein haufiges Problem nach Nierentransplantation dar. Unter bestimmten Umstanden kann diese ohne Therapie bleiben. Hohe Variabilitat der Tacrolimus-Talspiegel Schwankende Spiegel von Tacrolimus konnen verschiedene Ursachen haben und werden mit verschiedenen Endpunkten nach Nierentransplantation assoziiert. Unter Berucksichtigung dieses Koeffizienten erscheint es moglich, Risikopatienten zu identifizieren und intensiver zu kontrollieren und ggf. besser zu behandeln.

Background: Guidelines recommend regular measurements of the delivered hemodialysis dose Kt/V. Nowadays, automatic non-invasive online measurements are available as alternatives to the conventional method with blood sampling, laboratory analysis, and calculation. Methods:In a prospective clinical trial, three different methods determining dialysis dose were simultaneously applied: Kt/VDau (conventional method with Daugirdas’ formula), Kt/VOCM [online clearance measurement (OCM) with urea distribution volume V based on anthropometric estimate], and Kt/VBCM [OCM measurement with V measured by bioimpedance analysis (Body Composition Monitor)]. Results:1,076 hemodialysis patients were analyzed. The dialysis dose was measured as Kt/VDau = 1.74 ± 0.45, Kt/VOCM = 1.47 ± 0.34, and Kt/VBCM = 1.65 ± 0.42. The difference between Kt/VOCM and Kt/VBCM was due to the difference between anthropometric estimated VWatson and measured VBCM. Compared to Kt/VDau, Kt/VOCM was 15% lower and Kt/VBCM 5% lower. Kt/VDau was incidentally prone to falsely high values due to operative errors, whereas in these cases OCM-based measurements Kt/VOCM and Kt/VBCM delivered realistic values. Conclusions:The automated OCM Kt/VOCM with anthropometric estimation of urea distribution volume was the easiest method to use, but Kt/VBCM with measured urea distribution volume was closer to the conventional method.

It has not been established firmly whether dyslipidemia contributes independently to the progression of kidney disease. Lipid and lipoprotein parameters, including levels of total, HDL, and LDL cholesterol; triglycerides; lipoprotein(a); apolipoprotein A-IV; and the apolipoprotein E and A-IV polymorphisms, were assessed in 177 patients who had mostly mild to moderate renal insufficiency and were followed prospectively for up to 7 yr. Progression of kidney disease was defined as doubling of baseline serum creatinine and/or terminal renal failure necessitating renal replacement therapy. In univariate analysis, patients who reached a progression end point (n = 65) were significantly older and had higher serum creatinine and proteinuria as well as lower GFR and hemoglobin levels. In addition, baseline apolipoprotein A-IV and triglyceride concentrations were higher and HDL cholesterol levels were lower. Multivariate Cox regression analysis revealed that baseline GFR (hazard ratio 0.714; 95% confidence interval [CI] 0.627 to 0.814 for an increment of 10 ml/min per 1.73 m(2); P0.0001) and serum apolipoprotein A-IV concentrations (hazard ratio 1.062; 95% CI 1.018 to 1.108 for an increment of 1 mg/dl; P = 0.006) were significant predictors of disease progression. Patients with apolipoprotein A-IV levels above the median had a significantly faster progression (P0.0001), and their mean follow-up time to a progression end point was 53.7 mo (95% CI 47.6 to 59.8) as compared with 70.0 mo (95% CI 64.6 to 75.4) in patients with apolipoprotein A-IV levels below the median. For the apolipoprotein E polymorphism, only the genotype epsilon2/epsilon4 was associated with an increased risk for progression. In summary, this prospective study in patients with nondiabetic primary kidney disease demonstrated that apolipoprotein A-IV concentration is a novel independent predictor of progression.

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.

Renal transplant recipients (RTR) are considered representative of patients with chronic renal insufficiency (CRI) in general with respect to both reduced, progressively declining renal function, and increased risk for cardiovascular disease (CVD). In accord with this argument, we hypothesized that total (t) plasma concentrations of the putatively atherothrombotic amino acid homocysteine (Hcy) would be equivalent in RTR and CRI patients with comparable renal function. We determined plasma tHcy, folate, pyridoxal 5'-phosphate, and B12 concentrations, in addition to serum creatinine and albumin concentrations, in 86 chronic, stable RTR, and 238 patients with CRI. Within comparable ranges of serum creatinine (i.e. RTR=0.6-4.2 mg/dl; CRI=0.7-4.1 mg/dl), tHcy concentrations did not differ between the two groups (RTR=15.0 micromol/l; CRI=14.9 micromol/l, P=0.899). ANCOVA revealed that renal function, gauged as a simple creatinine measurement, was the major independent determinant of plasma tHcy concentrations, accounting for approximately 80-90% of the total variability in tHcy predicted by the full model (i.e. full model R(2)) containing, in addition to creatinine, the seven other potential explanatory variables. If controlled trials confirm that tHcy-lowering treatment reduces CVD events rates in RTR, these results should be applicable to CRI patients in general.

Hepatotoxic substance(s) removed by high-flux membranes enhances the positive acute phase response.BackgroundAcute phase proteins (APPs) are enhanced in end-stage renal disease patients (ESRD) requiring dialysis treatment. They are involved in a variety of pathologic processes like muscle proteolysis, cachexia, regulation of appetite, and atherosclerosis. They are predictive for mortality. APPs are not only makers but also active substances. They are mainly produced in liver cells and are primarily, but not exclusively, regulated by proinflammatory cytokines. To what extent hepatic APPs are influenced by uremic toxins is still unclear. Therefore, we investigated the effects of different ultrafiltrates (UFs) on the synthesis of α1-acid glycoprotein (AGP) in HepG2 cells.MethodsA cross-sectional as well as a crossover study with high-/low-flux membranes was conducted to investigate the impact of UFs on bioactivity of liver cell cultures. Metabolic activity (MTT test), cytotoxicity (lactate dehydrogenase release), and the positive APP AGP were measured in HepG2 cells.ResultsCultured hepatocytes treated with UFs from high-flux membranes exhibited a higher cytotoxicity (18.6 ± 0.3% high-flux vs. 13.9 ± 0.2% low-flux, P < 0.001) and a lower metabolic activity (29.3% high-flux vs. 50.3% low-flux, P < 0.001) in comparison with low-flux UFs. In addition, enhanced APP secretion could be observed under costimulatory conditions (high-flux 5.0 ± 0.7 vs. low-flux 3.1 ± 0.6 ng/μg protein, P < 0.05). The effects of high- and low-flux UFs were strongly expressed at the beginning and were still significantly different after 120 minutes of hemodialysis (HD) treatment. The cross-over experiments confirmed that UFs collected during high-flux HD had a higher capacity to stimulate AGP synthesis in liver cells.ConclusionThe effects of UFs from dialysis patients demonstrate that hepatotoxic substances can be removed by dialysis. Stimulating the acute phase response UF collected during high-flux HD had a higher impact on liver cells in comparison with low-flux UF. These substances are putative cofactors involved in cytokine regulation.

Objective: To evaluate the effects of prophylactic veno-venous hemofiltration (CVVH) in the absence of renal failure on multiple organ dysfunction syndrome after severe multiple trauma. Design: Prospective, randomized study. Setting: Intensive care unit (ICU) in a university hospital. Patients: Twenty-four patients with severe multiple trauma (injury severity score ≥27), no renal failure on admission and no contraindication for moderate heparinization. Interventions: Twelve patients received conventional treatment while 12 patients were treated additionally with isovolemic CVVH for 5 days starting within 24 h following trauma. Signs of organ dysfunction were assessed daily including monitoring of systemic hemodynamics by means of pulmonary artery catheterization during the first 5 days after trauma. Measurements and main results: Prophylactic CVVH did not affect the overall severity of organ dysfunction as assessed by MOF or APACHE II scores. However, the pattern of impaired organ systems was influenced by CVVH: while the post-traumatic decrease in platelet count in patients subjected to CVVH was more pronounced than in controls (e.g. day 4: control: 115,080±15,087, CVVH: 57,383±4,201 µl–1; p

It is generally assumed that hemodialysis adequacy is only minimally affected by increasing the dialysate flow rate (Qd). Recent in vitro studies showed that dialyzer urea clearance (Kd(urea)) may increase substantially more than expected in response to an increase in Qd. Because these studies implied that dialysis efficacy may benefit from greater Qds, we studied in vivo the effects of various Qds on the delivered dose of dialysis in 23 maintenance hemodialysis (MHD) patients. Hemodialysis was performed at Qds of 300, 500, and 800 mL/min for at least 3 weeks each, whereas specific dialysis prescriptions (treatment time, blood flow rate [Qb], ultrafiltration volume, and type and size of dialyzer) were kept constant. Delivered dose of dialysis, assessed by single-pool Kt/V (Kt/V(sp)) and double-pool Kt/V (Kt/ V(dp)), was measured at least three times for each Qd (218 measurements). Mean +/- SEM Kt/V(sp) was 1.19 +/- 0.03 at Qd of 300 mL/min, 1.32 +/- 0.04 at 500 mL/min, and 1.45 +/- 0.04 at 800 mL/min. The relative gains in Kt/V(sp) for increasing Qd from 300 to 500 mL/min and 500 to 800 mL/min were 11.7% +/- 8.7% and 9.9% +/- 5.1%, respectively. Kt/V(dp) increased at a similar percentage (11.2% +/- 8.9% and 10.3% +/- 5.1%, respectively). The observed gain in urea clearance by increasing Qd from 500 to 800 mL/min was significantly greater than the increase in Kd(urea) predicted from mathematical modeling (5.7% +/- 0.4%; P = 0.0008). Removal ratios for creatinine and the high-molecular-weight marker, beta(2)-microglobulin, were not affected by increasing Qd from 500 to 800 mL/min. The proportion of patients not achieving adequacy (Kt/V(sp) >/= 1.2) was reduced from 56% at Qd of 300 mL/min to 30% at 500 mL/min and further to 13% at 800 mL/min. It is concluded that increasing Qd from 500 to 800 mL/min is associated with a significant increase in Kt/V. Hemodialysis with Qd of 800 mL/min should be considered in selected patients not achieving adequacy despite extended treatment times and optimized Qbs.

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.

Hepatoactive substances eliminated by continuous venovenous hemofiltration in acute renal failure patients.BackgroundAcute renal failure (ARF) in critically ill patients is mostly part of a multi-organ failure. Therefore, the effects of renal replacement therapy on the liver are clinically important. We investigated the effects of ultrafiltrates of patients treated with continuous venovenous hemofiltration (CVVH) on liver cells in vitro.MethodsPatients with ARF were consecutively treated with CVVH using Multiflow60 (group I) or FH66 filters (group II). They were comparable with respect to diagnosis, age, sex, laboratory parameters, and renal replacement treatment, but were different in daily diuresis, serum levels, and blood flow. Ultrafiltrates were collected within the first 10 minutes after change of hemofilter. Proliferation (bromodeoxyuridine), vitality (lactate dehydrogenase), and acute-phase protein secretion of HepG2 cells were measured.ResultsUltrafiltrates changed liver cell function significantly compared with medium control. Proliferation (group I 29.8 ± 5.2% vs. group II 48.4 ± 6.6%, P < 0.05) and vitality (group I 78.7 ± 2.0% vs. group II 87.6 ± 1.7%, P < 0.01) of HepG2 cells were significantly different. On the one hand, the secretion of the negative acute-phase protein transferrin [group I 3.1 ± 0.2 (ng/μg protein) vs. group II 5.1 ± 0.5 (ng/μg protein), P < 0.01] was significantly reduced by Multiflow60 ultrafiltrates. On the other hand, positive acute-phase protein α1-acid glycoprotein was significantly stimulated by Multiflow60 ultrafiltrates [group I 2.6 ± 0.1 (ng/μg protein) vs. group II 1.7 ± 0.1 (ng/μg protein), P < 0.001].ConclusionThis study demonstrates hepatoactive mediators in the ultrafiltrates. They are hepatotoxic and influence acute-phase protein metabolism. Further studies have to elucidate the different effects in both groups and the analysis of the putative mediator(s). It remains a challenging task to consider therapeutic measures to optimize renal replacement therapy in critically ill patients.

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); p1-acid glycoprotein (AGP) (1.69±0.25) (pH 7.0) vs. 1.62±0.23 (pH 7.4) [ng/µg 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.

□ Der therapeutische Plasmaaustausch (TPA) ist ein extrakorporales Blutreinigungsverfahren zur Entfernung grosmolekularer Plasmabestandteile. Seit Ende der siebziger Jahre wurde die Plasmapherese bei einer Vielzahl von Erkrankungen eingesetzt, in deren pathophysiologischem Verstandnis humoralen Faktoren eine wesentliche Bedeutung zugeschrieben wird. □ Aus heutiger Sicht ist der Plasmaaustausch als adjuvante Therapie nur bei wenigen Entitaten in bestimmten Krankheitssituationen anerkannt: Antibasalmembranerkrankung, TTP/HUS, Guillain-Barre-Syndrom, Hyperviskositatssyndrom, chronische Polyneuropathie bei IgG- und IgA-Gammopathie, chronisch inflammatorische demyelinisierende Polyneuropathie und Myasthenia gravis.

□ Hintergrund Die idiopathische Retroperitonealfibrose ist gekennzeichnet durch eine fortschreitende Proliferation und Fibrosierung retroperitonealen Gewebes. Durch eine zunehmende Kompression und Ummauerung benachbarter Strukturen kommt es dabei im Verlauf der Erkrankung zu zahlreichen Komplikationen.

Eine der wichtigsten Kontrastmittelnebenwirkungen ist die akute Verschlechterung einer bereits bestehenden Nierenfunktionseinschrankung. Die Inzidenz liegt in Abhangigkeit der Grunderkrankung zwischen 20% und 100%. In experimentellen und klinischen Studien wurden zahlreiche medikamentose Therapieansatze zur Pravention der Kontrastmittelnephropathie untersucht. In der vorliegenden ubersicht werden diese Masnahmen hinsichtlich ihrer klinischen Relevanz bewertet. Als Schlusfolgerung dieser Studien kann als einzig gesicherte Masnahme zur Protektion der Kontrastmittelnephropathie bei Risikopatienten (Ausgangskreatinin > 1,5 mg/dl) eine ausreichende Hydratation empfohlen werden. Sie wird mit 1 ml/kg KG/h mittels 0,45% NaCl zwolf Stunden vor und nach Kontrastmittelapplikation durchgefuhrt. Bei Patienten mit hohergradiger Nierenfunktionseinschrankung (Serumkreatinin > 3,5 mg/dl) und gleichzeitigem Vorliegen einer zusatzlichen Risikokonstellation (zum Beispiel Diabetes mellitus) wird eine Hamodialysebehandlung nach Kontrastmittelgabe empfohlen. Der Wertr der Dialysebehandlung ist allerdings nicht durch kontrollierte Studien gesichert.

A 17-year-old female with a 5-year history of disseminated lupus erythematosus has remained without immunosuppressive therapy for the last 3 years. She was admitted to the hospital for acute abdominal pain, generalized edema, and rapidly developing dyspnea and somnolence. Although all symptoms were consistent with active SLE, septicemia was suspected because of leukocytosis (20,000/microliters), greatly elevated C-reactive protein (45 mg/dl), and normal complement values (C3 0.74 g/l, C4 0.21 g/l). Directly after bacterial blood cultures were prepared, a combined treatment was instituted consisting of plasmapheresis (3 x 2.1 l against fresh frozen plasma), antibiotics, prednisolone, and cyclophosphamide following the last plasmapheresis. Within three days cerebral function returned to normal, edema improved, and CRP fell to 0.5 mg/dl. The blood cultures and pericardial effusion displayed meningococcal colonies.

The effect of different immunosuppressive drugs (prednisolone, azathioprine, cyclosporin A) on liver carbohydrate metabolism in the rat was investigated. Daily administration of prednisolone (3 mg/kg body weight) and azathioprine (2 mg/kg body weight) intraperitoneally for 2 weeks caused significantly lower liver glycogen content than that in NaCl-treated controls. Liver glucose and lactate content, as well as plasma glucose, glucagon, and serum insulin concentration of these animals, remained unchanged. There were no differences in any of these parameters between cyclosporin A (15 mg/kg body weight)-treated and vehicle (olive oil/ethanol)-treated animals. Prednisolone caused significantly lower glucose production in isolated rat hepatocytes using Na-pyruvate as the substrate, whereas glucose production was unchanged in hepatocytes of azathioprine-treated rats using pyruvate or L-serine as substrates. Glucose production from pyruvate or serine was significantly inhibited by cyclosporin A compared to the vehicle, but did not differ from the effects of azathioprine and prednisolone. Lactate production was significantly lower in cyclosporin-treated animals than in those given either the vehicle or azathioprine. Cyclosporin A completely reversed the inhibition of hepatocyte glycogen consumption caused by the vehicle. However, glycogen production in the presence of cyclosporin A was comparable to the effects of prednisolone and azathioprine. Finally, hepatocyte ketone body production using pyruvate as the substrate was higher in the presence of all immunosuppressive drugs. In the presence of serine, acetoacetate production increased in rats treated with 50 mg/kg body weight cyclosporin A, and beta-hydroxybutyrate production in animals receiving 15 and 50 mg/kg body weight cyclosporin A.

The European APD Outcome Study (EAPOS) is a 2-yr, prospective, multicenter study of the feasibility and clinical outcomes of automated peritoneal dialysis (APD) in anuric patients. A total of 177 patients were enrolled with a median age of 54 yr (range, 21 to 91 yr). Previous median total time on dialysis was 38 mo (range, 1.6 to 259 mo), and 36% of patients had previously been on hemodialysis for >90 d. Diabetes and cardiovascular disease were present in 17% and 46% of patients, respectively. The APD prescription was adjusted at physician discretion to aim for creatinine clearance (Ccrea) ≥60 L/wk per 1.73 m 2 and ultrafiltration (UF) ≥750 ml/24 h during the first 6 mo. Baseline solute transport status (D/P) was determined by peritoneal equilibration test. At 1 yr, 78% and 74% achieved Ccrea and UF targets, respectively; median drained dialysate volume was 16.2 L/24 h with 50% of patients using icodextrin. Baseline D/P was not related to UF achieved at 1 yr. At 2 yr, patient survival was 78% and technique survival was 62%. Baseline predictors of poor survival were age (>65 yr; P = 0.006), nutritional status (Subjective Global Assessment grade C; P = 0.009), diabetic status ( P = 0.008), and UF ( P = 0.047). Time-averaged analyses showed that age, Subjective Global Assessment grade C and diabetic status predicted patient survival with UF the next most significant variable (risk ratio, 0.5/L per d; P = 0.097). Baseline Ccrea, time-averaged Ccrea, and baseline D/P had no effect on patient or technique survival. This study shows that anuric patients can successfully use APD. Baseline UF, not Ccrea or membrane permeability, is associated with patient survival. E-mail: e.a.brown@imperial.ac.uk

Cell culture studies and investigations in mice that overexpress either human or mouse apolipoprotein A-IV (apoA-IV) revealed anti-atherogenic properties of apoA-IV. An association between low apoA-IV concentrations and coronary artery disease in humans was demonstrated; therefore, apoA-IV may also play an antiatherogenic role in humans. Because apoA-IV is markedly elevated in dialysis patients, patients with the earliest and modest stages of renal impairment were studied to assess the association of apoA-IV with GFR and atherosclerotic complications. GFR was measured by the use of iohexol in 227 non-nephrotic patients with different degrees of renal impairment. ApoA-IV increased significantly with decreasing GFR and was already elevated in earliest stages of renal disease (GFR > 90 ml/min per 1.73 m2). Multiple linear regression analysis identified renal function parameters (GFR, creatinine, and urea) as the most important determinants of apoA-IV levels in serum of these patients. Twenty-six patients had already experienced 36 atherosclerotic events. Logistic regression analysis identified three variables associated with atherosclerotic complications: age, apoA-IV, and gender. Each 1 mg/dl increase of apoA-IV decreased the odds ratio for an atherosclerotic complication by 8% (P = 0.011). The data clearly show that the anti-atherogenic apoA-IV starts to increase during the earliest phases of renal insufficiency, which makes apoA-IV an early marker of renal impairment.

Conflicting data have been reported concerning the independent association between proteinuria and plasma total homocysteine (tHcy) levels, particularly among chronic renal disease (CRD) patients with a normal range serum creatinine. Studies of this potential relationship have been limited by failure to assess true GFR, failure to assess proteinuria in a quantitative manner, or arbitrary restriction of the range of proteinuria examined. We examined the potential independent relationship between plasma tHcy levels and a wide range of quantitatively determined proteinuria (i.e., 0.000-8.340 g/day), among 109 CRD patients with a normal range serum creatinine (range; 0.8-1.5 mg/dl; median=1.2 mg/dl). Glomerular filtration rate (GFR) was directly assessed by iohexol clearance, and plasma status of folate, pyridoxal 5'-phosphate, and B12, along with serum albumin, were also determined. Linear modeling with ANCOVA revealed that proteinuria was not independently associated with tHcy levels (partial R=0.127; P=0.201), after adjustment for potential confounding by GFR (partial R=0.408; P

Moderate hyperhomocysteinemia is very frequent in renal patients. Aside from homocysteine (HCY) itself, the metabolites methylmalonic acid (MMA) and cystathionine (CYS) supply further information about disturbances in HCY metabolism. In two groups of renal patients, transplant and hemodialysis patients, we measured HCY, MMA and CYS and evaluated their diagnostic value for impaired HCY metabolism due to vitamin deficiency and renal insufficiency. We investigated serum samples from 63 transplant patients and 38 patients undergoing hemodialysis. HCY, MMA and CYS were assayed by gas chromatography-mass spectrometry, vitamin B6 by HPLC, B12 and folate by chemiluminescence immunoassay. The determination of HCY, MMA, and CYS in renal patients provides specific information about intracellular disturbances of HCY metabolism. The frequency of increased metabolite levels in renal patients was much higher than the frequency of lowered vitamin concentrations in serum. Furthermore, the metabolite levels in transplant patients were only moderately increased, whereas they were strongly increased in patients on hemodialysis (HCY 19.2 vs. 28.8 micromol/l, MMA 292 vs. 1025 nmol/l, CYS 733 vs. 2711 nmol/l). Our findings may support the use of MMA determination in the diagnosis of vitamin B12 deficiency in renal patients. Compared to vitamin B12 deficiency, renal dysfunction itself appears to cause only a modest elevation in serum MMA. Regression analysis revealed that the moderate elevation of HCY and CYS in transplant patients is mainly a consequence of impaired remethylation of HCY to methionine with activated transsulfuration, whereas the mildly elevated MMA level is attributable to renal dysfunction. In patients on hemodialysis, all three metabolites were markedly elevated, indicating a strongly disturbed HCY metabolism. Based on a backward regression, we discovered that the HCY metabolism was strongly disturbed by renal insufficiency and vitamin deficiency. The markedly elevated HCY level was mainly attributable to functional vitamin B12 deficiency indicated by high MMA, and the strong CYS elevation was due to renal dysfunction and inhibition of this pathway by low levels of vitamin B6. In conclusion, besides HCY, the determination of MMA and CYS levels supports an early diagnosis of B-vitamin deficiency in renal patients. MMA is a more sensitive indicator of intracellular vitamin B12 deficiency than vitamin B12 in serum.

High lipoprotein(a) (Lp(a)) serum concentrations and the underlying apolipoprotein(a) (apo(a)) phenotypes are risk factors for cardiovascular disease in the general population as well as in patients with renal disease. Lp(a) concentrations are markedly elevated in patients with end-stage renal disease. However, nothing is known about the changes of Lp(a) depending on apo(a) size polymorphism in the earliest stages of renal impairment. In this study, GFR was measured by iohexol technique in 227 non-nephrotic patients with different degrees of renal impairment and was then correlated with Lp(a) serum concentrations stratified according to low (LMW) and high (HMW) molecular weight apo(a) phenotypes. Lp(a) increased significantly with decreasing GFR. Such an increase was dependent on apo(a) phenotype. Only renal patients with HMW apo(a) phenotypes expressed higher median Lp(a) concentrations, i.e., 6.2 mg/dl at GFR >90 ml/min per 1.73 m2, 14.2 at GFR 45 to 90 ml/min per 1.73 m2, and 18.0 mg/dl at GFR

Hepatic amino acid uptake, urea and glucose production are increased in acute uraemia. It has been shown that this metabolic pattern is mediated by glucocorticoids. Accordingly, the administration of the antiglucocorticoid RU 38486 to acutely uraemic rats resulted in a reduction of serum urea-N and glucose levels. To clarify whether this effect is due to a reduction in hepatic gluconeogenesis we examined the effect of the antiglucocorticoid RU 38486 on urea and glucose formation in isolated hepatocytes from sham-operated (SHAM) and bilaterally nephrectomized (BNX) rats receiving RU 38486 or the vehicle only. Hepatic glucose production in BNX rats was considerably increased from Na-pyruvate (+ 79%), alanine (+ 174%), glutamine (+158%), and serine (+ 87%) compared with SHAM animals. Concomitantly, hepatic urea formation was also enhanced from amino acid substrates in acutely uraemic rats. When uraemic animals were treated with RU 38486, glucose production from amino acids and Na-pyruvate was reduced to the range of SHAM animals or even lower. This effect could not be demonstrated in SHAM-operated controls. A comparable decrement in hepatic urea production was observed in BNX rats treated with the antiglucocorticoid. Thus, glucocorticoids appear to play a key role in the abnormal hepatic urea and glucose production of acutely uraemic rats.

The effects of end-tidal concentrations of 1.45% isoflurane and 2.12% enflurane on splanchnic blood flow (electromagnetic flow probes), oxygen (O2) extraction and surface PO2 (Clark-type electrode), and hepatic metabolism (organic acids) were compared in an animal model relevant to humans. Eighteen laparotomized, ventilated pigs, anesthetized and paralyzed with ketamine/flunitrazepam and pancuronium, were studied. Enflurane caused significantly (P less than 0.05) greater decreases in mean arterial pressure, cardiac output, and superior mesenteric arterial, portal, and total hepatic blood flows. In addition, hepatic arterial blood flow decreased during enflurane administration but increased markedly (40%) during isoflurane administration. However, mean surface PO2 of liver and small intestine decreased to similar degrees (20%) during isoflurane and enflurane. Summary histograms of surface PO2 values were leftward shifted but did not show O2 values in the hypoxic range (0-5 mm Hg). Except for a decrease in hepatic lactate uptake during enflurane, there were no changes in either hepatic uptake or release of organic acids during anesthesia with either agent. These data show that splanchnic O2 supply is better maintained during isoflurane than during enflurane. Although this was not reflected in differences in tissue oxygenation and metabolism, decreased portal and hepatic venous O2 contents during enflurane indicate that an increase in preportal and hepatic oxygen extraction was necessary to preserve tissue oxygenation.

Plasma levels of granulocyte lactoferrin, myeloperoxidase, and elastase in α1-proteinase inhibitor complex were compared with C3a and C5a levels in 10 patients undergoing cardiopulmonary bypass. At the end of the operation, plasma levels of lactoferrin increased from 97.0 ± 22.8 to 1257 ± 139.8 ng/ml, myeloperoxidase increased from 37.1 ± 4.3 to 170.9 ± 34.9 ng/ml, and elastase in α-proteinase inhibitor complex rose from 89.4 ± 7.4 to 437.8 ± 97.3 ng/ml. There was also a significant anaphylatoxin formation. To investigate the relationship between complement and granulocyte activation, patients undergoing cardiopulmonary bypass received the calcium channel blocker nifedipine (orally and intravenously) and the antiplatelet drug dipyridamole. The continuous infusion of nifedipine (5.91 ± 0.53 μg/kg body weight per hour) caused significantly lower levels of elastase in α-proteinase inhibitor complex and lactoferrin but not anaphylatoxin. Dipyridamole was without effect on complement and granulocyte activation during cardiopulmonary bypass. Our data demonstrate inhibition of granulocyte activation during cardiopulmonary bypass by continuous infusion of nifedipine, even in the presence of complement activation.

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.

Various endocrine and metabolic disturbances associated with long standing uremia persist after kidney transplantation or arise from the use of immunosuppressive drugs. Hyperlipidemia for long time being implicated as the cause of corticosteroids is also observed in renal transplant recipients treated with cyclosporin A monotherapy. After conversion from cyclosporin to azathioprine serum cholesterol and triglyceride concentration fall, and elevation of LDL-cholesterol may also be reversed. There is a tendency for higher HDL-cholesterol in azathioprine and prednisolone treated transplant patients. Those patients who are at risk for clinically significant cholesterol elevations can be predicted by their pretransplant lipid levels, specifically the LDL-fraction. Risk-benefit ratio of conversion and of treatment with lipid-lowering drugs, especially with lovastatin, should be carefully examined, also in view of glucose intolerance. Higher incidence of diabetes mellitus requiring insulin therapy in cyclosporin treated transplant recipients has been reported. Cyclosporin may cause toxic effects on pancreatic beta-cells resulting in inhibition of insulin secretion. High doses of cyclosporin induce inhibition of glycogen synthesis in rat liver. Glucose intolerance is reversible after reduction of cyclosporin dose or conversion to azathioprine. Therefore glucose metabolism in kidney transplant recipients treated with cyclosporin should be carefully followed. Immunosuppressive therapy may affect reproductive function, arachidonate metabolism and renin-angiotensin-aldosterone system as well as posttransplant calcium and phosphate metabolism. Endocrine and metabolic abnormalities are associated with long standing uremia. After successful kidney transplantation several observations are normalized but further complications arise from the use of immunosuppressive drugs. The present paper reviews various endocrine and metabolic disturbances described following renal transplantation.

The potential role of an oral administration of nifedipine was investigated in the rat. Therefore, animals were fed on a nifedipine-containing or control diet for 12 days. Nifedipine caused a significant decrease of liver glycogen (47.9 +/- 4.9 vs 132.6 +/- 17.1 micrograms/mg protein), whereas liver glucose (213.1 +/- 15.3 vs 110.4 +/- 6.4 micrograms/mg) and lactate (44.8 +/- 4.1 vs 26.5 +/- 1.8 nmol/mg) concentrations increased. Various concentrations of nifedipine failed to influence glycogenolysis but stimulated gluconeogenesis in isolated rat hepatocytes. Blood lactate and pyruvate levels were significantly elevated in the nifedipine pretreated rats, whereas ketone bodies remained constant. Nifedipine pretreatment also increased the rates of excretion of various electrolytes and water followed by significantly lower plasma sodium, potassium, phosphate, and normal glucose values. We conclude that nifedipine-induced liver glycogenolysis may deteriorate glucose tolerance in patients with an already impaired carbohydrate metabolism.

Plasma levels of main granulocyte components of patients after cadaveric renal transplantation were compared 9 days postoperative with the plasma levels of patients undergoing aortofemoral and iliacofemoral bypass operation or abdominal surgery. Lactoferrin values were significantly lower in patients under immunosuppression with cyclosporine and prednisolone, whereas plasma levels of myeloperoxidase were comparable in all 3 groups of patients. Plasma E-alpha 1 PI values were significantly lower in patients undergoing bypass operation compared to abdominal surgery but did not differ from patients undergoing cadaveric kidney transplantation. Within 22 days postoperatively, there was no difference in the plasma levels of main granulocyte components in patients after kidney transplantation with and without postoperative complications. In vitro incubation of heparinized whole blood and isolated granulocytes obtained from healthy subjects in the presence of CsA, azathioprine, or prednisolone were performed. Only CsA caused inhibition of spontaneous degranulation of polymorphonuclear neutrophils showing significant lower elastase and lactoferrin release. However, in vivo administration of CsA and prednisolone in transplant patients displayed no effect on in vitro degranulation of both whole blood samples and isolated granulocytes. Our data demonstrate that CsA after in vitro incubation inhibits spontaneous granulocyte degranulation but not after in vivo administration. However, in vivo administration of CsA and prednisolone reduces lactoferrin release under certain conditions, e.g., postoperative stress or during hemodialysis therapy.

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.

Evaluation of renal Kt/V as a marker of renal function in predialysis patients.BackgroundThe use of renal Kt/V (r-Kt/V) as an indicator for the need of dialysis initiation has been recommended in the NKF-DOQI guidelines. In analogy to clinical practice in peritoneal dialysis, a fall of r-Kt/V below a threshold of 2.0 per week may indicate inadequate renal toxin elimination. However, there are no studies linking r-Kt/V with other parameters of glomerular filtration rate (GFR) in predialysis patients, and the validity of r-Kt/V as parameter for timing of dialysis initiation is unknown.MethodsRenal function was assessed repeatedly in 125 patients (N = 465 measurements). In predialysis patients (r-Kt/V

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.

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.

In operative trauma or severe inflammatory responses, polymorphonuclear leukocytes release lysosomal proteinases extracellularly and into the circulation (Duswald et al., 1985). Immediately after surgery a decrease of elastase in complex with α1-proteinase inhibitor (Eα1PI) is observed due to the elimination of the infection focus (Jochum et al., 1984). During hemodialysis treatment there is also an increase of E- α1PI (Horl et al., 1983; Horl and Heidland 1984) depending on the membrane material of the dialyzer used (Horl et al., 1985a and b). There was also demonstrated that polymorphonuclear leukocytes release myeloperoxidase and lactoferrin during hemodialysis treatment (Horl et al., 1986). Corticosteroids can stabilize membranes, inhibit locomation, phagocytosis and degranulation of polymorphonuclear leukocytes (Smolen and Weissmann 1978; Dunham et al., 1977). In the present study we evaluated plasma levels of main granulocyte components of patients following cadaveric renal transplantation. The effect of different immune suppressive drugs on the release of main granulocyte constituents was investigated in vitro and also during hemodialysis.