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The objective of this study was to determine the pharmacokinetic profile of meropenem in automated peritoneal dialysis (APD) patients. In 6 patients without peritonitis, a single dose of 0.5 g of meropenem was applied intraperitoneally (i.p.) or intravenously (i.v.) and concentrations in serum and dialysate were measured at specified intervals over 24 h with high-performance liquid chromatography-mass spectrometry. The mean maximum concentrations of meropenem in serum ( C max ) were 27.2 mg/liter (standard deviation [SD], ±6.9) and 10.1 mg/liter (SD, ±2.5) and in dialysate were 3.6 mg/liter (SD, ±2.3) and 185.8 mg/liter (SD, ±18.7) after i.v. and i.p. administrations, respectively. The mean areas under the curve from 0 to 24 (AUC 0–24 ) of meropenem in serum were 173.5 mg · h/liter (SD, ±29.7) and 141.4 mg · h/liter (SD, ±37.5) ( P = 0.046) and in dialysate were 42.6 mg · h/liter (SD, ±20.0) and 623.4 mg · h/liter (SD, ±84.1) ( P = 0.028) after i.v. and i.p. administrations, respectively. The ratios for dialysate exposure over plasma exposure after i.v. and i.p. treatments were 0.2 (SD, ±0.1) and 4.6 (SD, ±0.9), respectively ( P = 0.031). A mean target value of 40% T >MIC (time for which the free meropenem concentration exceeds the MIC) for clinically relevant pathogens with EUCAST susceptibility breakpoints of 2 mg/liter was reached in serum after i.p. and i.v. administrations and in dialysate after i.p. but not after i.v. administration. The present data indicate that low i.p. exposure limits the i.v. use of meropenem for PD-associated peritonitis. In contrast, i.p. administration not only results in superior concentrations in dialysate but also might be used to treat systemic infections.

Malnutrition is a relevant risk factor for mortality for patients on maintenance hemodialysis treatment. In a retrospective study including 377 patients who began hemodialysis treatment between 1986 and 2001, we assessed the prevalence of different statuses of nutrition and the impact of the initial status of nutrition on the change in body weight and patient survival. We found an inverse relationship between body mass index (BMI, kg/m2) and the gain in body weight and BMI within 12 months of hemodialysis treatment. Underweight and normal weight patients had a substantial increase in these parameters, greatest in underweight subjects, whereas overweight and obese patients showed only a moderate increase or none (P =.0019, P =.00036). Adjusted mortality rates showed an inverse correlation with the initial BMI (P

Objective: To assess the tolerability, efficacy and ease of use of epoetin-beta in a cartridge formulation, self-administered subcutaneously via a pen injector (Reco-Pen®), in patients with end-stage renal disease. Design and Setting: This was a multinational, multicentre, open, single-group study of 12 to 16 weeks’ duration. Patients: 420 adult patients with end-stage renal disease in the maintenance phase of epoetin treatment for anaemia. Interventions: Reco-Pen® epoetin-beta multidose formulation. Patients had previously been receiving treatment with subcutaneous or intravenous epoetin at a dosage of ≥2500 IU/week. Main Outcome Measures and Results: Drug tolerability was evaluated by the frequency of adverse events (AEs), local tolerability, changes in blood pressure and laboratory variables. Efficacy was assessed using blood transfusion requirements and changes in haematological variables. The ease of use of the Reco-Pen® was also assessed. A total of 40% of evaluable patients (n = 418) reported ≥1 AE, although few AEs were considered to be drug related (5%). The incidence of serious AEs was 13%. A very small percentage of patients reported local intolerability (2%). No relevant changes in blood pressure, laboratory variables, haematocrit and haemoglobin levels were apparent during treatment with epoetin-beta. Four percent of patients required blood transfusions. Most patients (92%) found the Reco-Pen® device easy to use and 89% found it easier to use than their previous self-administration method. The majority of patients (81%) rated injections as pain free. Conclusions: Reco-Pen® appears to be as well tolerated and effective as other conventional methods of epoetin administration. However, it has the added benefits of pain reduction at the injection site and improved convenience, which can encourage patients to self-administer their medication subcutaneously.

1. Blood leptin levels are increased in obese subjects and seem to play a major role in the hypothalamic regulation of appetite and energy expenditure. 2. We measured plasma leptin levels in a cohort of 46 patients on maintenance haemodialysis treatment and 26 control subjects. 3. Higher body mass indices were associated with higher plasma leptin levels in both groups. 4. The increase was more pronounced in the dialysis group than in the control group (P = 0.001), leading to inappropriately high plasma levels. 5. Haemodialysis with low flux cellulosic dialysers did not result in a decrease in plasma levels, while dialysis with high flux dialysers and haemodiafiltration led to a substantial reduction of the initial value to 76.95 ± 14.89% (P = 0.013) and 62.90 ± 24.94% (P = 0.001) respectively. 6. Our data suggest that high flux dialysis membranes can decrease plasma leptin levels and that inappropriately high plasma leptin levels may play a role in the nutrition of haemodialysis patients.

We report the case of a woman with relapsed glioblastoma multiforme (GBM) who recently gave birth. She announced her pregnancy shortly after the sixth cycle of a dense regimen of temozolomide, prescribed for treating the first recurrence of glioblastoma. Three years ago, in April 2008, she had undergone gross total resection of a glioblastoma multiforme in the postcentral region of the right hemisphere and had subsequently received treatment according to the actual standard therapy consisting of radiotherapy up to 60 Gy with concomitant and adjuvant temozolomide. The complete amount of temozolomide given before this pregnancy was 20.9 mg/m2. Nevertheless, she delivered a 1890 g child by caesarean section in the 32/6 week of pregnancy. The child showed no anomalies and is developing normally under close surveillance by paediatricians.

Laura Merlini,1 Giacomo Cartenì,2 Stefano Iacobelli,3 Caterina Stelitano,4 Mario Airoldi,5 Peter Balcke,6 Felix Keil,7 Ferdinand Haslbauer,8 Laura Belton,9 Beatriz Pujol10 1Department of Medical Oncology, Ospedale Civile S, Bortolo, Vicenza, 2Department of OncoHematology, Azienda Ospedaliera di Rilievo Nazionale "Antonio Cardarelli", Napoli, 3Department of Medical Oncology, Ospedale Clinicizzato SS Annunziata, Chieti, 4Department of Hematology, Azienda Ospedaliera "Bianchi Melacrino Morelli", Reggio Calabria, 5Department of Medical Oncology, Azienda Ospedaliero Universitaria Le Molinette, Torino, Italy; 61st Medical Department, General Hospital St Pölten and Karl Landsteiner Institute of Oncology, St Pölten, 73rd Medical Department (Hematology and Oncology), Hanusch Krankenhaus der Wiener Gebietskrankenkasse, Vienna, 8Department of Oncology, Landeskrankenhaus Vöcklabruck, Vöcklabruck, Austria; 9Contract biostatistician, Amgen Ltd, Uxbridge, UK; 10Research and Development Haematology/Oncology, Amgen Europe, Zug, Switzerland Purpose: To describe the prevalence and management of anemia in cancer patients. Methods: This cross-sectional, observational survey was conducted in Italy and Austria. Centers prespecified one day, during a 4-month enrollment window, to report specific data collected during normal clinical practice for patients with non-myeloid tumors attending for chemotherapy (±radiotherapy) treatment. The primary endpoint was the prevalence of anemia as determined using a prespecified algorithm: hemoglobin (Hb) ≤10 g/dL on/within 3 days prior to visit; ongoing anemia treatment; physician diagnosis of anemia, together with ≥1 anemia symptom. Results: Between November 18, 2010 and March 18, 2011, data for 1412 patients were collected (Italy n = 1130; Austria n = 282). Most patients (n = 1136; 80%) had solid tumors; 809 (57%) had received ≤ 3 chemotherapy cycles. The prevalence of anemia was 32% (95% confidence interval: 29.4%–34.2%); 196 patients (14%) were deemed anemic based on Hb ≤10 g/dL, 131 (9%) on ongoing anemia treatment, and 121 (9%) on physician diagnosis/anemia symptom. Overall, 1153 patients (82%) had Hb data; mean (standard deviation [SD]) Hb levels were 11.7 (1.7) g/dL. In total, 456 patients (32%) had anemia symptoms: fatigue (n = 392; 28%), depression (n = 122; 9%), and dyspnea (n = 107; 8%) were most common. Fifty-one patients (4%) had had their current chemotherapy cycle delayed due to anemia. On visit day, or ≤ 28 days prior, 91 (6%), 188 (13%), and 81 patients (6%) had evidence of whole blood/red blood cell transfusion, erythropoiesis-stimulating agent use, or iron use, respectively. Conclusion: On the prespecified study day, one-third of patients with non-myeloid tumors undergoing chemotherapy were found to be anemic and 13% had evidence of erythropoiesis-stimulating agent use then or in the 28 days prior. Keywords: erythropoiesis-stimulating agent, hemoglobin, iron, management, transfusion&nbsp

Peritonitis is a major complication of peritoneal dialysis (PD) being associated with hospitalization, catheter loss, technique failure, and increased mortality. Data on incidence rates and risk factors for peritonitis episodes vary between centers. In seven Austrian PD units clinical and laboratory data on each peritonitis episode were collected from all patients (n = 726) who performed PD between January 2000 and December 2009. The peritonitis incidence rate was 0.32 episodes/patient-year. In a multivariate analysis the risk of peritonitis was decreased by 57% in patients treated with oral active vitamin D (HR 0.43; 95% CI 0.28-0.64). Renal disease classified as "other or unknown" (HR 1.65; 95% CI 1.08-2.53) and serum albumin

The MDR1 gene, a multidrug resistance gene, codes for P-glycoprotein which pumps hydrophobic drugs out of the cells. Since cyclosporins also bind to P-glycoprotein and might be pumped by this transmembrane protein, we determined the expression of the MDR1 gene in the lymphocytes of 32 patients with renal transplants. MDR1 RNA expression of lymphocytes was measured by slot blot analysis and compared to the expression of drug-sensitive KB-3-1 cells and multidrug-resistant KB-8-5 cells. MDR1 RNA expression was detected in the lymphocytes of 9 (28%) patients, whereas no expression was seen in the remaining 23 patients. No association between MDR1 RNA expression and transplant function or hematological parameters was observed. However, none of the 6 patients who had transplants for more than 40 months expressed the MDR1 gene in their lymphocytes. In conclusion, expression of the MDR1 gene does occur in lymphocytes of patients with renal transplants and might reduce the immunosuppressive efficacy of cyclosporins through enhanced efflux of cyclosporins.

Purpose The European Medicines Agency recommends limiting the hemoglobin (Hb) concentration to 10 to 12 g/dL in adults with chronic kidney disease (CKD) receiving erythropoiesis-stimulating agents such as epoetin theta. This postauthorization study assessed the incidence and intensity of cardiovascular events, including ischemic stroke, in patients receiving epoetin theta for anemia associated with CKD. A secondary end point was adverse drug reactions, including pure red cell aplasia. Methods In this prospective, noninterventional, multinational cohort study, consecutive patients with advanced or end-stage renal disease and receiving epoetin theta were followed up for 6 months. Data on reportable adverse events (RAEs) ( cardiac disorders, cardiac failure, myocardial infarction, and ischemic stroke and respective subterms), epoetin theta dosage, and Hb concentrations were collected. A post hoc exploratory analysis assessed the incidences of RAEs according to tertiles for individual mean Hb concentration (≤10.7, >10.7–11.47, and >11.47 g/dL for low, intermediate, and high, respectively) and mean weekly epoetin theta dosage (≤62, >62–125, and >125 IU/kg/wk for low, intermediate, and high). Findings Data from 1039 patients were included (577 men, 462 women; mean age, 68.7 years). A total of 101 RAEs were documented in 89 patients (8.6%), for an event rate of 0.1985/person–year. Sixty-four patients (6.1%) died; none of the deaths was considered related to epoetin theta use. The incidence of RAEs was lowest at intermediate Hb concentrations (6.2%) compared with low (11.3%) and high (7.8%) Hb concentrations. The incidence of ischemic stroke was 1.5% at high Hb concentrations versus 0.6% at both the low and intermediate Hb concentrations. The incidence of any RAE was greater in the high-dose group (10.1%) than in the intermediate-dose (8.0%) and low-dose (7.6%) groups. The risk for any cardiovascular RAE or ischemic stroke was greatest in the high-dose/high-Hb group (13.3%), followed by high dose/low Hb (12.6%) and low dose/low Hb (12.1%). The risks for RAEs were lowest at high dose/intermediate Hb (3.8%) and low dose/intermediate Hb (5.3%). The event rate of adverse drug reactions other than the predefined RAEs was 0.0161/person–year. No cases of pure red cell aplasia were reported. Implications The findings from the present study suggest that, for maintaining the optimal target Hb concentration (10–12 g/dL according to the current summary of product characteristics for epoetin theta; 10–11.5 g/dL according to the current guideline from Kidney Disease Improving Global Outcomes) in anemic adults with CKD, the lowest approved, effective dose epoetin theta should be used.

1. Serum levels of erythropoietin and the immune parameters tumour necrosis factor-α, soluble interleukin-2 receptor, interleukin-2, interleukin-6 and interferon-γ were measured in patients with rheumatoid arthritis. 2. Out of 69 patients, 44 had anaemia with serum haemoglobin concentrations of 10.8 (SD 1.2) g/dl. In these patients erythropoietin levels were significantly higher than in non-anaemic patients [51.97 (SD 23.9) versus 26.06 (SD 11.9) m-units/ml; P < 0.0001; control patients: 18.1 (SD 13.8) m-units/ml]. Mean soluble interleukin-2 receptor activity was elevated in all patients with rheumatoid arthritis [1324 (SD 715) units/ml; control patients: 480 (SD 75) units/ml; P < 0.001] and was significantly higher in the anaemic group than in the non-anaemic group [1562 (SD 662) versus 696 (SD 402) units/ml; P < 0.0001]. The serum activity of soluble interleukin-2 receptor showed an inverse correlation with haemoglobin (r = 0.79; P < 0.0001) and a positive correlation with erythropoietin (r = 0.70, P < 0.0001). 3. Elevated serum tumour necrosis factor-α levels were found in 19 anaemic patients [20.6 (SD 9.1) pg/ml]. Concentrations of tumour necrosis factor-α in serum showed an inverse correlation with haemoglobin (r = 0.57, P < 0.001) and a positive correlation with erythropoietin (r = 0.46, P < 0.05). Interleukin-6 was detected in seven anaemic patients [21 (SD 14) pg/ml] and interleukin-2 activity in three anaemic patients (12, 16 and 14 units/ml, respectively). Interferon-γ was not detected in any of the patients investigated. 4. The present study supports the concept that in patients with rheumatoid arthritis the responsiveness to erythropoietin is impaired. Immune mechanisms may be operative and point to a pivotal role for tumour necrosis factor-α.

We report on the first documented outbreak of leptospirosis in Austria. In July 2010, four cases of serologically confirmed leptospirosis occurred in athletes after a triathlon held in Langau. Heavy rains preceded the triathlon (rainfall: 22 mm). The index case (Patient A) was a 41-year-old previously healthy male, who was admitted to hospital A on July 8 with a four-day history of fever up to 40°C that began 14 days after attending the triathlon event. On July 7, patient B, a 42-year-old male, was admitted to the same hospital, with signs and symptoms of kidney failure. Hemodialysis was performed every other day for 3 weeks. While the serum drawn on the day of admission was negative for antibodies against Leptospira, a specimen from July 28 tested positive with Leptospira interrogans. On July 11, patient C, a 40-year-old male, was admitted to hospital B for nephritis. On July 14, patient D, a 44-year-old male, was admitted to hospital C with a ten days history of intermittent fever, mild dry cough and headache. Our report underlines that in Austria recreational users of bodies of freshwater must be aware of an existing risk of contracting leptospirosis, particularly after heavy rains. The suppressive influence of a triathlon on the immune system is well documented and therefore an outbreak in this population group can be seen as a sensitive indicator concerning possible risk for the general population.

Upon interaction of whole blood with foreign materials, heterogeneous protein films are deposited onto the artificial surface (eg, hemodialysis membranes). The composition of these protein films subsequently affects various processes, eg, thrombogenesis or activation of the complement system. We developed an in vitro model with which we can identify and study proteins interacting with capillaries during hemodialysis. Using this model we studied the cuprophane dialyzer GFS 120 (CP) and the polymethylmetacrylate membrane Filtryzer B2-1.2 (PMMA). Heparinized whole blood from healthy young volunteers was dialyzed on an extracorporeal dialysis machine. After the dialysis procedure the adsorbed material was eluted from the hemodialysis membranes by different eluants and subsequently analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. A number of proteins could be identified in the eluates of both membrane types. Interestingly, platelet glycoproteins could only be found in PMMA eluates. Albumin, IgG, and antithrombin III were mainly present in the cuprophane eluates. Fibrinogen was demonstrable in all eluates, but in relatively low amounts, and the protein was significantly degraded. Degradation products of antithrombin III and complement factor 3 could also be identified. The process causing the degradation has not yet been identified, but may be due to proteases released from damaged cells. © 1993 John Wiley & Sons, Inc.

One of the initial events upon contact of blood with artificial surfaces is the deposition of a heterogeneous protein layer on the foreign material. Proteins of the blood coagulation system are known to be involved in these reactions. In this paper the adsorption of two contact coagulation factors [high-molecular weight kininogen (HK) and factor XI (FXI)] and fibrinogen on to three different haemodialysis membranes [CA 130, cellulose acetate; Prima H, cuprophane; and Filtryzer B2-1.3, poly(methyl methacrylate) (PMMA)] was addressed. Heparinized blood, drawn from healthy volunteers, was mixed with the purified radiolabelled proteins and was dialysed with an extracorporeal dialysis machine using CH3COO− as the dialysis medium. Haemodialysis was followed by an extensive rinsing procedure. Then the haemodialysis capillaries were tested for bound radioactivity. Fibrinogen, HK and FXI were absorbed on to all three haemodialysis membranes. However, quantitative differences were observed for the three membranes. The adsorption data correlate well with results obtained in various in vitro studies using other experimental models. Pretreatment of the haemodialysis system with saline, heparin or albumin did not reduce the adsorption of the coagulation factors tested, as may have been expected from in vitro tests.

Anti-interleukin-1α autoantibodies in hemodialysis patients. IL-1 activity is increased in hemodialysis patients and interest has recently been focused on IL-1 antagonism in various clinical settings. We studied the presence of anti-IL-1α autoantibodies in sera from 49 hemodialysis patients, 159 kidney graft recipients and 89 chronic renal failure patients without renal replacement therapy. Within the three month study period 32.6% of the hemodialysis patients were found to present with anti-IL-1α autoantibodies, in contrast to 5.6% of kidney graft recipients, 8.9% of chronic renal failure patients, and only 1.4% of healthy subjects. The presence of these autoantibodies was neither associated with primary kidney disease nor with the type of dialysis membrane we used. In addition, in antibody positive patients a pronounced increase of IL-1α serum levels within a dialysis session from 14.8 ± 4.7 pg/ml to 26.4 ±11.2 pg/ml (P < 0.0005) was observed, contrasting to the more even increase from 14.1 ± 3.1 pg/ml to 19.3 ± 12.7 pg/ml (P < 0.05) in the antibody negative group. Neither clinical symptoms due to adverse effects of IL-1α nor some influence on erythropoiesis mediated by IL-1 α could be envisaged. Thus, we believe, that anti-IL-1α autoantibodies, present in high frequency in hemodialysis patients, have a neutralizing effect on IL-1α in these patients.

Reduced oxygen tension is regarded as the primary physiologic signal for the production of erythropoietin (EPO). There is little information available about early changes of EPO production in man due to severe hypoxia. The purpose of the present study was to examine the time course of EPO in serum of patients with acute cardiogenic pumonary edema (ACPE). In 29 patients (seventy-five ± six years, mean age ± SEM) who were hospital ized within two hours after onset of symptoms of ACPE, serum EPO concentra tions were monitored for up to seventy-two hours. At the moment of admission all patients showed significantly increased EPO concentrations of 121 ± 64 mU/mL (mean ±SEM) compared with a healthy population (15-35 mU/mL). Twenty- three patients who recovered within thirty minutes (group A) exhibited a quick return of their EPO serum levels to normal. The remaining 6 patients (group B) had a protracted clinical course and their EPO concentration showed a further increase up to the end of the observation period. The comparative monitoring of concentrations of alpha-1-proteinase inhibi tor, antithrombin III, C-reactive protein, fibronectin, hapotoglobin, and trans errin in serum and plasma revealed no significant changes. Thus a major contribution of fluid shifts into or from the intravascular compartment to the observed changes in EPO concentration seems to be unlikely. The data suggest that the production and release of EPO in the kidneys due to altered oxygen delivery is a fast-responding mechanism.

Effect of conjugated estrogens on platelet function and prostacyclin generation in CRF. In a double-blind, randomized, placebo-controlled cross-over study, we investigated in seven patients with chronic renal failure the effect of conjugated estrogens (0.6 mg/kg/day for 5 days) on template bleeding time and on thromboxane A 2 (TxA 2 ), β-thromboglobulin (β-TG) and prostacyclin (PGI 2 ) concentrations in blood emerging from the template bleeding time incisions. Administration of conjugated estrogens resulted in a significant shortening of the bleeding time in six out of seven patients with a maximum effect 7 and/or 14 days following treatment. Both TxA 2 (measured as thromboxane B 2 , TxB 2 ) and β-TG release in bleeding time blood were significantly higher following administration of conjugated estrogens as compared to placebo administration. No difference was seen in endothelial PGI 2 (measured as 6-keto-prostaglandin F 1α ) formation when patients were treated with conjugated estrogens as compared to placebo administration over the 28 day observation period. We conclude that in patients with chronic renal failure, infusion of conjugated estrogens results in a significant shortening of the bleeding time together with an increase in platelet reactivity, as indicated by an increase of TxA 2 and β-TG concentration in the microvasculature. No effect was seen on PGI 2 production, thereby excluding a major effect on vascular prostaglandin metabolism.

1. The generation of the plasma SC5b—9 complex (the soluble form of the membrane attack complex) during haemodialysis was studied in 29 patients together with markers of the classical (C4d fragment) and alternative (Bb fragment) pathways and the common iC3b fragment. 2. In the patients dialysed with Hemophan and Cuprophan membranes, a rapid increase in the plasma levels of SC5b—9 complex, Bb fragment and iC3b fragment occurred within 15 min of the initiation of the haemodialysis procedure. The SC5b—9 complex and the Bb fragment concentrations remained at a plateau until 120 min thereafter. The iC3b fragment level showed a continual decline. 3. The C4d fragment concentrations remained unchanged, indicating that generation of the membrane attack complex is most likely due only to activation of the alternative pathway. 4. The generation of the membrane attack complex occurred throughout the full haemodialysis period. In patients treated with Polysulfon membranes no statistically significant variation in these components was noted. 5. The study shows that the membrane attack complex may be generated during the full period of the haemodialysis session and is a stable index of biocompatibility. 6. Moreover, it seems be involved directly in haemodialysis-associated phenomena.

Upregulation of a lymphoid serine protease in kidney allograft recipients. The presence of a putative, cytotoxicity-linked lymphoid serine esterase (SE) has been studied in 79 kidney graft recipients. Peripheral blood lymphocytes (PBL) bearing an N-α-benzyloxy carbonyl-L-lysine thiobenzyl ester (BLT)-specific SE were evaluated by a novel cytochemical staining method. A characteristic of post-allograft patients was an increased presence of SE containing granules in PBL. In 46 patients with stable graft function SE + PBL were 33.41 ± 10.34% (controls: 26.30 ± 5.22%, P < 0.0025), SE + CD4+ 4.32 ± 3.85% (controls 2.13 ± 1.52%, P < 0.0025) and SE + CD8+ T cells 47.68 ± 18.64% (controls: 28.50 ± 6.50%, P < 0.0005). In those graft recipients undergoing a rejection episode a marked upregulation of SE activity could be observed when compared to the stable graft group: SE + PBL were 59.91 ± 10.89% (P < 0.0005), SE + CD8+ 74.30 ± 10.79% (P < 0.0005) and SE + CD4+ T cells 28.56 ± 13.50% (P < 0.0005). In 10 cases this increase of SE activity was observed with a time lag of up to 37 days prior to the onset of clinical or biopsy proven rejections, promptly decreasing in response to methylprednisolone antirejection therapy. In patients with recurrent rejection episodes and subsequent graft loss, a repeating increase of SE activity indicated a failure of therapeutic agents. In allograft recipients suffering from a viral infection, usually identified as cytomegalovirus, in comparison to those with a rejection episode, high levels of SE + PBL were found (67.10 ± 12.72%, P < 0.1) due to the upregulation of SE + CD8+ lymphocytes (76.30 ± 12.05%, P < 0.35) and a low-grade SE activity of CD4+ cells (12.20 ± 8.13%, P < 0.0025) in concordance with an inverted CD4/CD8 ratio. Our results underline the assumption that BLT-SE is closely associated to lymphocyte activation/cytotoxic function.

End-stage renal failure and long-term hemodialysis treatment promote the development of genetically conditioned porphyria cutanea tarda (PCT). The clinical manifestation is triggered off by unknown factors coexisting with renal insufficiency and hemodialysis. Iron overload is often associated with the disease and is thought to play a key role in its pathogenesis. Iron removal by deferoxamine infusions is regarded as the treatment of choice for patients who cannot undergo repeated phlebotomy procedures and has been successfully used in patients with normal renal function. We report a case of hemodialysis-related PCT and iron overload in whom repeated venesections were contraindicated on account of severe anemia and treatment with deferoxamine led to a striking improvement of symptoms.

In general, nonrheumatic atrial fibrillation is associated with a high risk of stroke. However, its impact on stroke in the setting of chronic hemodialysis treatment is insufficiently addressed in the literature. We assessed the incidence of stroke among 430 chronic hemodialysis patients and the impact of atrial fibrillation and various other potential risk factors on stroke in a retrospective study covering 1,111.16 patient-years. The overall incidence of stroke was 3.78/100 patient-years. Among patients with chronic atrial fibrillation without any antithrombotic therapy besides regular dialysis anticoagulation, the stroke incidence was 1.0/100 patient-years and did not differ statistically significantly from the rate among patients without this arrhythmia, in whom the incidence was 2.8/100 patient-years (p = 0.220). Conversely, the overall rate of stroke incidence per 100 patient-years was statistically significantly higher in patients with diabetic nephropathy (6.46, p = 0.0036), age >65 years (5.90, p = 0.0001), moderate to severe hypertension (6.8, p = 0.0017), weight gain of >2 kg between dialyses as a marker of poor patient compliance (6.47, p = 0.0433), and antithrombotic therapy with salicylates or warfarin (8.33, p = 0.0002), as compared with corresponding groups without these risk factors. Our data suggest that in contrast to other risk factors nonrheumatic atrial fibrillation in itself is not associated with an increased risk of stroke in patients on maintenance hemodialysis treatment.

The prevalence of pulmonary thromboembolism at autopsy was assessed in a retrospective study of a cohort of 185 patients undergoing maintenance hemodialysis treatment who died in the last decade. The overall frequency of thromboembolism was 12.43% in the dialysis population, which statistically was significantly less than in a control group of 8,051 nondialysis patients (21.77%; P = 0.0023). Moreover, pulmonary thromboembolism was less frequently fatal or contributing to death in the dialysis group than in the control group (P = 0.039). The prevalence of pulmonary thromboembolism in the dialysis group remained statistically unchanged over the 10-year period and was independent of a steady increase in the percentage of patients receiving recombinant erythropoietin therapy and the average hematocrit values. The occurrence of preterminal pulmonary thromboembolism was associated with a shorter period since onset of hemodialysis treatment and with infection as cause of death (P = 0. 031; P = 0.029, respectively). No statistically significant influence of the type of basic renal disease, type of dialysis anticoagulation, or dialysis access could be found. Our data suggest that, at least in the preterminal stage, the introduction of recombinant erythropoietin within the last decade had no substantial influence on the prevalence of pulmonary thromboembolism.

1. Plasma levels of endothelin were measured in 30 patients with chronic renal failure, 32 patients on chronic haemodialysis treatment and 25 renal graft recipients with stable renal graft function. 2. In patients with chronic renal failure as well as in patients on regular haemodialysis treatment, mean plasma levels of endothelin were significantly increased (4.59 ± 2.09 pg/ml, 10.08 ± 3.12 pg/ml, respectively) when compared with normal subjects (1.88 ± 0.6 pg/ml, P 3. In the group with chronic renal failure a positive correlation between the plasma level of endothelin and the plasma concentration of creatinine was observed (P 4. Renal graft recipients on cyclosporin A with stable renal graft function had a normal plasma level of endothelin suggesting that cyclosporin A nephrotoxicity is not mediated by endothelin. 5. Hypertensive patients with chronic renal failure or on regular haemodialysis and hypertensive renal graft recipients did not differ from the corresponding normotensive population with regard to the plasma level of endothelin, demonstrating that an increased plasma level of endothelin does not play a major role in the pathogenesis of renal hypertension.

Twenty-three patients with analgesic nephropathy and apparent cessation of drug abuse were tested for blood acetaminophen and salicylate on the occasion of routine renal control examinations. In 12 patients (mean creatinine level 2.74 +/- 1.09 mg/dl) no deterioration of renal function was noted within a 1-year observation period (Group 1). In 11 patients a significant progression of renal insufficiency was observed (mean creatinine level rose from 3.86 +/- 1.06 to 6.40 +/- 3.18 mg/dl within the same observation period; Group 2). Blood tests for acetaminophen and salicylate were positive in 2 patients of Group 1 and in 9 patients of Group 2 (chi 2 = 7.326), p less than 0.01). Our data emphasize the importance of a continuous analgesic abuse hidden from the medical staff with regard to the progression of renal insufficiency in analgesic nephropathy.

The pharmacokinetics and dose response of recombinant human erythropoietin (rhEPO), administered intravenously and subcutaneously, were studied in chronic haemodialysis (HD) patients and in patients on chronic ambulatory peritoneal dialysis (CAPD). Furthermore, two products differing in the presence of albumin as preservative were compared. Although the pharmacokinetics differed after intravenous and subcutaneous administration, the dose response was the same. There is no statistically significant difference in the pharmacokinetics between the rhEPO in HD and CAPD, nor had the presence of albumin as preservative an influence on the pharmacokinetics.

1. We determined plasma levels of histamine in uraemic patients and examined their correlation with the presence of pruritus. 2. In 27 patients with chronic renal failure, plasma histamine levels were analysed by radioimmunoassay and were compared with those of 40 healthy adult subjects. The control population showed plasma histamine concentrations of 185 ∓ 33 pg/ml, which were significantly lower than those of the patients with renal insufficiency. The highest levels (552 ± 116 pg of histamine/ml) were found in 16 patients with chronic renal failure (mean serum creatinine 5.1 ∓ 1.0 mg/dl) and severe itching. 3. Twelve patients with pronounced pruritus who were on maintenance haemodialysis (serum creatinine 9.2 ±1.2 mg/dl) had a mean plasma histamine concentration of 515 ± 81 pg/ml. Fifteen patients on regular haemodialysis (serum creatinine 9.0 ± 1.5 mg/dl) and who experienced itching had plasma histamine levels (322 ±40 pg/ml) which were significantly lower (P < 0.01) than those of the patients with pruritus but which were elevated compared with those of the control population (P < 0.01). 4. No correlation could be found between increased plasma histamine levels and the type of dialysis membrane used or the method of sterilization of the membrane. 5. Haemodialysis alone did not reduce plasma histamine concentrations, although high concentrations could be detected in the ultrafiltrate. In six patients a rapid decrease in plasma histamine concentration from 565 ∓ 134 pg/ml to within the normal range could be detected after 60 min of combined haemodialysis and haemoperfusion. 6. Our results show that increased plasma levels of histamine are found in patients with renal insufficiency and pruritus, and we conclude that this mediator might be involved in the genesis of uraemic pruritus.

Recombinant human erythropoietin activates a broad spectrum of progenitor cells. Twenty uremic patients on regular hemodialysis received recombinant human Erythropoietin (rhEPO) in a dosage of 50 U/kg body wt (N = 9) and 80 U/kg body wt (N = 11), respectively, three times weekly. The number of circulating hemopoietic progenitor cells colony-forming unit-granulocyte-erythrocyte-macrophage (CFU-mix), burst-forming unit-erythroid (BFU-E) and colony-forming-granulocyte-macrophage (CFU-GM) in peripheral blood were assayed weekly by means of a commonly applied in vitro clonal assay. A significant increase of peripheral CFU-mix, BFU-E and CFU-GM could be observed within one week of supplementation therapy in both groups. The increase of BFU-E was followed by a rise of hematocrit within four and three weeks, respectively. These results suggest that the stimulatory in vivo effect of rhEPO administered in therapeutical doses is not restricted to the erythroid lineage but also includes progenitor cells committed to the myeloid lineage (CFU-GM) as well as the multipotent progenitors CFU-mix. The increment of circulating progenitor cells was seen with a dosage of 80 U/kg body wt and 50 U/kg body wt as well.

Decreased postheparin lipolytic activity in renal transplant recipients with cyclosporin A. The patterns of hyperlipidemia in renal transplant recipients (RTRs) are more variable than in the uremic state, showing increases in both very low-density lipoprotein (VLDL) and low density lipoprotein (LDL). This has been attributed, at least in part, to immunosuppressive therapy, especially to treatment with corticosteroids. Postheparin lipolytic activity (PHLA) was determined in 28 RTRs. Sixteen patients presenting with hyperlipidemia comprised group A, who were aged 49.8 ± 13.5 years, and had a cholesterol of 8.24 ± 1.86 mmol/liter, triglycerides of 6.02 ± 3.33 mmol/liter. Twelve patients presenting cholesterol and triglyceride values within the normal range were in group B, and were aged 48.6 ± 13.3 years. All RTRs received cyclosporin A (CsA) twice daily orally, which were divided in two equal doses and adjusted to provide CsA blood trough levels (RIA) in a range of 250 to 350 ng/ml. Twenty-one RTRs were additionally treated by alternate-day corticosteroids, whereas seven patients had CsA on their sole immunosuppressive agent. PHLA (µmol free fatty acids/ml/hr, given 10 and 20 min after 100 U/heparin kg body wt intravenously) was commonly reduced in RTRs (group A at 10/20 min: 5.6 ± 1.1/5.26 ± 1.2; group B: 8.26 ± 2.91/8.38 ± 3.44) as compared to the values obtained in healthy controls (15.3 ± 2.9/17.2 ± 5.0). This was mainly due to a reduction of the activity of the hepatic triglyceride lipase, and to a minor extent to a reduced activity of peripheral lipoprotein lipase. There was no statistically significant difference of PHLA in RTRs with or without corticosteroid treatment. Postheparin lipolytic activity is commonly decreased in renal transplant recipients. This effect does not depend on low corticosteroid administration, but may be caused by CsA medication.

Accumulation of oxalic acid resulting in elevated plasma levels is a common finding in uraemic patients. Since vitamin B6 is an important coenzyme in oxalic acid metabolism the influence of vitamin B6 administration on plasma oxalic acid levels was investigated. Vitamin B6 was administered to eight chronic haemodialysis patients with secondary hyperoxalaemia. Mean plasma oxalic acid concentration decreased from 149.5 +/- 67 mumol/l to 99.0 +/- 36.4 mumol/l within 2 weeks and to 93.8 +/- 33.1 mumol/l after 4 weeks of pyridoxine treatment (P less than 0.01) the mean reduction being 46% (32.0-56.1%). The decrease in plasma oxalic acid levels was most pronounced in patients with the highest pretreatment values. Two patients who received pyridoxine therapy prior to the beginning of the study had low initial values of plasma oxalic acid concentrations and showed no further decline.

Pre-eclampsia is a severe complication in pregnancy, manifested by hypertension, proteinuria and oedema, and in the most severe cases leading to fetal death. Immunological mechanisms are generally assumed to be of major importance in the genesis of the disease. Foidart showed anti-laminin antibodies to be involved in preeclampsia. [ 11. Circulating immune complexes [2] and complement activation [3] as well as alterations in T-cell subsets [4] and suppressor activity [5] have also been observed, but still there remains much uncertainty about the pathophysiological mechanisms involved. IL-2 is an important cytokine in the T-cell pathway [6] as it is released by antigenstimulated T cells and enhances alloantigen reactivity by augmentation of cellular cytytoxic function. The question of whether increased cytokine release can be used as a diagnostic marker for an ongoing alteration of maternofetal immune response prompted us to study the serum activity of IL-2 in pregnant women suffering from pre-eclampsia.

In our study of three pregnancies in kidney transplant patients we aimed to evaluate changes in cyclosporin requirements and to explain the nature of these changes

Die Pathogenese der EPH-Gestose ist weiterhin unklar, es wird jedoch vermutet, das immunologische Vorgange dieser Erkrankung zugrunde liegen. Verschiedene Faktoren wie eine gesteigerte Anzahl der T-Helperzellen bei verminderter bzw. normaler Zahl an Suppressorzellen [1], eine erhohte Killerzellaktivitat [2] und positive zirkulierende Immunkomplexe [3] stutzen diese Annahme. Interleukin-2 (IL-2) wird nach Antigenstimulierung unter Prasenz des Monkines Interleukin 1 aktivierten T-Zellen synthetisiert und bedingt eine Proliferation der T-Zellpopulation [4].

In 6 male subjects the diurnal variation of urinary oxalic acid excretion was studied after ingestion of chocolate, a food stuff rich in oxalic acid. The ingestion of chocolate caused a striking but transient increase in urinary oxalic acid excretion due to its absorption in the upper gastrointestinal tract. The peak excretion rates occurred 2-4 h after the intake of the chocolate. The peak values were 235% of the fasting excretion rate in the trial with 50 g chocolate and 289% in the trial with 100 g chocolate and reached the amounts found in cases with primary hyperoxaluria. The administration of ranitidine had no influence on oxalic acid absorption. The transient hyperoxaluria observed seems to be an important factor for the formation of calcium oxalate calculi in patients on risk for stone disorders.

Background Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. Methods A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. Results Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. Conclusion There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.

SummaryThe formation of prostacyclin (PGI2) and thromboxane A2 and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the micro vasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F1α (6-keto-PGF1α) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI2 formation in chronic uraemia. Formation of thromboxane B2 (TxB2) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the a-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is - at least partially - due to an acquired defect of the platelet a-granule release and an increased generation of PGI2 in the micro vasculature.

The concentration of oxalic acid was determined in the plasma of 15 patients with conservatively treated chronic renal insufficiency and 17 dialysis patients. A cumulation of oxalic acid was found in connection with uraemia. The extent to which plasma oxalic acid concentrations were raised depended on the degree of renal insufficiency and was directly related to the plasma creatinine values in all patients with or without dialysis. In the patients with chronic renal insufficiency the median plasma oxalic acid concentration was 74.4-18.5 (control group 27.0 +/- 7.4) mumol/l. In the dialysis patients the levels were even higher, at 137.5 +/- 56.0 mumol. By means of haemodialysis it was possible to lower the plasma oxalic levels by about the same amount as creatinine concentrations. The higher plasma oxalic acid concentrations seem to be an important pathogenetic factor in the formation of uraemic calcification in various organs. The therapeutic consequences are to increase the duration and frequency of dialysis and to remedy possible vitamin B6 deficiency.