Immunogenicity and safety of the 13-valent Pneumococcal Conjugate vaccine in 23-valent pneumococcal polysaccharide vaccine-naive and pre-immunized patients under treatment with chronic haemodialysis: a longitudinal quasi-experimental phase IV study.

OBJECTIVE: To benchmark the immunogenicity of pneumococcal conjugated vaccine (PCV-13) versus pneumococcal polysaccharide vaccine (PPV-23) in haemodialysis patients pre-vaccinated or not with PPV-23. METHODS: The study is a longitudinal quasi-experimental phase IV study in chronic haemodialysis patients aged ≥50 years. Total (ELISA) and functional (opsonophagocytic assay) antibodies after pneumococcal vaccination were quantified at baseline, and after 28 and 365 days. Of 201 eligible patients, 155 were included. Patients were divided in four groups. PPV-23 naive patients were randomized to PPV-23 (40) or PCV-13 (40) vaccination. PPV-23-pre-vaccinated patients were categorized as being vaccinated more (40) or less (35) than 4 years before the study and all received PCV-13. RESULTS: Patients among the four groups had a significant ELISA antibody response for most serotypes that remained significant up to day 365 versus baseline. In PPV-23-naive patients, ELISA antibody titres were significantly higher among PCV-13 versus PPV-23 recipients for six serotypes (1.85-2.34-fold) after 28 days, and remained significantly higher for one serotype (6A, 1.57-fold) after 365 days. Following PCV-13 vaccination, increase in ELISA antibody titres was significantly higher among PPV-23-naive versus PPV-23-pre-vaccinated patients for 12 serotypes after 28 days (1.68-7.74-fold) and remained significantly higher in ten serotypes (1.44-3.29-fold) after 365 days. CONCLUSION: Immune response after PPV-23 and PCV-13 remains significant for at least 1 year in non-PPV-23-pre-vaccinated patients. Among vaccine-naive haemodialysis patients PCV-13 seems more immunogenic than PPV-23. Immune response to PCV-13 is weaker in PPV-23-pre-vaccinated compared with vaccine-naive patients.

Dialysability of sugammadex and its complex with rocuronium in intensive care patients with severe renal impairment.

BACKGROUND: Renal excretion is the primary route for the elimination of sugammadex. We evaluated the dialysability of sugammadex and the sugammadex-rocuronium complex in patients with severe renal impairment in the intensive care unit (ICU). METHODS: Six patients in the ICU with acute severe renal impairment received general anaesthesia for transoesophageal echocardiography, to replace their tracheal tubes, or for bronchoscopy. Five of the six patients were in the ICU after cardiac/vascular surgery and one for pneumonia-induced respiratory failure. They all received rocuronium 0.6 mg kg(-1), followed 15 min later by sugammadex 4.0 mg kg(-1). Two patients were studied for two dialysis episodes and four patients for four episodes. Rocuronium and sugammadex concentrations were measured in plasma and dialysate at several time points before, during, and after high-flux dialysis. Dialysis clearance in plasma and dialysate, and reduction ratio (RR) (the extent of the plasma concentration reduction at the end of a dialysis episode when compared with before dialysis) were calculated for each dialysis episode. RESULTS: Dialysis episodes lasted on average 6 h. Observed RRs indicated mean reductions of 69% and 75% in the plasma concentrations of sugammadex and rocuronium, respectively, during the first dialysis episode. Reductions were around 50% during sequential dialysis episodes. On average, dialysis clearance of sugammadex and rocuronium in blood was 78 and 89 ml min(-1), respectively. CONCLUSIONS: Haemodialysis using a high-flux dialysis method is effective in removing sugammadex and the sugammadex-rocuronium complex in patients with severe renal impairment.

C.E.R.A. safety profile: a pooled analysis in patients with chronic kidney disease.

BACKGROUND: C.E.R.A., a continuous erythropoietin receptor activator, is a long-acting erythropoiesis-stimulating agent (ESA) that is approved for the treatment of renal anemia. This analysis evaluated the safety profile of C.E.R.A. in comparison to that of other ESAs in patients with chronic kidney disease (CKD). METHODS: Safety parameters were analyzed in a pooled population comprising all patients with CKD on dialysis and not on dialysis from the completed Phase II and Phase III studies in the C.E.R.A. clinical program (Phase II/III population); patients were treated with either C.E.R.A. (n = 1,789) or comparator ESA (n = 948). Differences between treatment groups in safety parameters were identified by either a 2% difference in incidence between groups, or a statistically significant difference between groups (p < or = 0.05 with the Fisher's exact test, which was used as a conservative screening tool). To assess changes in safety findings over time, long-term safety data were analyzed from patients who were given the option to enter long-term safety studies upon completing their initial Phase II/III study (safety extension population). RESULTS: Compared with the C.E.R.A. group, the incidence of adverse events (AEs) was higher in the comparator ESA group in the Phase II/III population (C.E.R.A. vs. comparator ESA, 89.5% vs. 91.8%, p = 0.067), and significantly so in the safety extension population (93.0% vs. 95.8%, p = 0.003). The incidence of serious AEs was significantly higher in the comparator ESA group than in the C.E.R.A. group in both analysis populations (Phase II/III population, 37.8% vs. 42.4%, p = 0.021; safety extension population, 53.3% vs. 59.7%, p = 0.001). However, there was no consistent pattern of clinical events that could explain these differences between the treatment groups. CONCLUSION: Analysis of safety events in patients with renal anemia receiving long-term treatment with C.E.R.A. shows a safety profile comparable to that of other ESAs.

Preservation of renal function after heart transplantation: initial single-center experience with sirolimus.

BACKGROUND: Long-term survivors of heart transplantation are often confronted with chronic kidney disease, by definition related to the intake of calcineurin-inhibitors. Sirolimus is increasingly proposed as an alternative immunosuppressive agent due to its absence of nephrotoxicity. METHODS: Between November 2002 and November 2003, 9 adult heart transplant candidates with moderate to severe chronic renal disease were switched from cyclosporine to sirolimus. The conversion scheme consisted of an immediate stop of cyclosporine and an 8-mg loading dose of sirolimus, followed by 3 mg/d; after 1 week, the sirolimus dose was adjusted to maintain trough levels between 5 and 15 microg/L. The majority of patients were on corticosteroids, and on either azathioprine or mycophenolate mofetil. At conversion, the mean serum creatinine level was 2.11 (+/-0.4) mg/dL and the mean glomerular filtration rate (GFR) was 32 (+/-7) mL/min/1.73 m(2). Prior to conversion, the renal dysfunction was predominantly stable. RESULTS: After conversion, there were 7 dropouts (75%) due to several side effects related to sirolimus: edema (n = 2), general discomfort (n = 2), delayed wound healing (n = 1), cardiac thrombus (n = 1), and diarrhea (n = 1). The median treatment time with Sirolimus, therefore, was only 4.0 months. While on sirolimus, the renal function of all patients remained unchanged or showed even some improvement. Retrospective nephrological review revealed severe renal artery stenoses in 2 patients and serious generalized abdominal and renal atheromatosis in 7 patients. No cardiac dysfunction was seen. CONCLUSION: Conversion from cyclosporine to sirolimus was problematic due to sirolimus side effects, occurring at any time after the switch. One should also question whether chronic kidney disease after heart transplantation is routinely caused by the administration of calcineurin-inhibitors, in view of the generalized renal and abdominal atheromatosis.

The 13C-octanoic acid breath test: validation of a new noninvasive method of measuring gastric emptying in rats.

Currently available rat models for measuring gastric emptying are hampered by the necessity to kill the animals at the end of each experiment, which makes repetitive testing impossible. We have developed and validated a noninvasive test model, adapted from the 13C-octanoic breath test in humans, for repetitive measurements of gastric emptying in rats. Male Wistar rats were trained on a fixed protocol to eat a piece of pancake doped with 1 microg 13C-octanoic acid after 12 h fasting, and to stay thereafter in cylindrical glass cages. Breath tests were performed by a fully automated system of computer-guided switching valves, which collected consecutive breath samples. All breath samples were analysed by gas chromatography and isotope mass spectrometry. The area under the curve (AUC) from the cumulative 13CO2 excretion from 0 to 6 h was determined by the trapezium method to calculate the gastric half-emptying times (t(1/2)). Inter-day variability was determined. The effect of subcutaneous or intraperitoneal injection of saline was studied. The test was further validated for pharmacological interventions by oral administration of cisapride and parenteral administration of atropine, to induce, respectively. acceleration and delay of gastric emptying. Mean gastric emptying times +/- SD of 24 rats were 119.3 +/- 28.2 min, 138.7 +/- 26.0 min, and 124.5 +/- 30.9 min on three different test days. The mean coefficient of variation of three repeated measurements in the same 24 rats was 17.5%. No significant differences were observed after subcutaneous or intraperitoneal injection of saline. In a second test series of eight rats, cisapride significantly accelerated gastric emptying (mean t(1/2) 112.7 +/- 33.1 min, P < 0.05), while atropine caused a significant delay (mean t(1/2) 205.9 +/- 24.9 min, P < 0.05) when compared to control test results (mean t(1/2) 140.7 +/- 16.7 min) in the same rats. We validated the 13C-octanoic breath test to study gastric emptying in rats. This test method obviates the necessity to kill laboratory animals and allows repetitive measurements of gastric emptying to study its physiology or pathophysiology as well as the effect of pharmacological agents.

Dyspepsia and gastroparesis in chronic renal failure: the role of Helicobacter pylori.

AIMS: Many patients with chronic renal failure have dyspeptic symptoms. In the present study, we assessed the Helicobacter pylori (Hp) status, dyspeptic symptoms and gastric emptying rates in uremic patients. The present study was undertaken to compare chronic renal failure patients not under dialysis therapy (predialysis), hemodialysis (HD) patients and peritoneal dialysis (PD) patients for these variables and to search for a possible causative role of Hp. METHODS: We used a standardized questionnaire to assess dyspeptic symptoms. Gastric emptying rates were determined by the 13C-octanoic acid breath test. HD patients were examined outside a dialysis session, PD patients were examined with a "full" abdomen. Specific Helicobacter pylori IgG was measured by a second-generation enzyme-linked immunosorbent assay. RESULTS: Sixty-six HD patients. 58 predialytic patients and 28 PD patients were included. Prevalences of Hp infection were highest in HD patients (46.2%) and predialysis patients (42.3%) compared to PD patients (28.6%) (p < 0.02). On the contrary, the prevalence of dysmotility-like dyspepsia was higher in PD patients (67.9%) when compared to HD patients (33.3%) (p < 0.01) and predialytic patients (53.6%) (difference not significant). Neither dyspepsia nor delayed gastric emptying were related to the presence of Helicobacter pylori IgG antibodies. CONCLUSION: A positive Helicobacter status based on serology was not related to the presence of dyspepsia or gastroparesis in uremic patients, whether on dialysis therapy or not. Dyspeptic complaints as well as gastroparesis are most prevalent in patients on peritoneal dialysis. The physiopathological mechanisms and clinical impact of these findings merit further investigation.

Gastric emptying of solids in cirrhotic and peritoneal dialysis patients: influence of peritoneal volume load.

INTRODUCTION: A delay in gastric emptying rate has been reported in peritoneal dialysis patients, often normalizing after evacuation of the dialysate. To evaluate the effect of the intraperitoneal volume, we compared this finding with a cirrhotic model in which gastric emptying was studied before and after a large-volume paracentesis. METHODS AND DESIGN: We used the 13C-octanoic acid breath test to measure gastric half-emptying time (T1/2) for solids in patients with alcoholic cirrhosis, non-diabetic peritoneal dialysis patients, and a control population (asymptomatic volunteers). Cirrhotic patients underwent the test on two consecutive mornings before and after an evacuating paracentesis. Peritoneal dialysis patients were studied twice on consecutive days: once with the dialysate present intra-abdominally ("full"), and once with an emptied abdomen ("empty"). Biochemical analysis was carried out on blood samples before the first test. All cirrhotics underwent a 13C-aminopyrine breath test to assess residual liver function. RESULTS: Gastric emptying in cirrhotics showed no difference before or after paracentesis (median T1/2 108.0 min v. 117.9 min), but it was delayed significantly versus normal in both tests. There was no correlation with biochemical parameters, Child-Pugh score, or 13C-aminopyrine breath test results. Gastric half-emptying times of "full" peritoneal dialysis patients (median T1/2 103.1 min) were significantly higher than those of "empty" peritoneal dialysis patients (median T1/2 68.9 min) and asymptomatic volunteers (median T1/2 60.1 min). "Empty" peritoneal dialysis patients showed no gastroparesis. CONCLUSION: In alcoholic cirrhotic patients with ascites, gastric emptying of solids is delayed, independently of the volume of ascites. In peritoneal dialysis patients, gastric emptying was delayed when "full" and normalized after drainage of the dialysate.

Dyspepsia and gastric emptying in chronic renal failure patients.

AIMS: Chronic renal failure (CRF) patients frequently suffer from dyspeptic complaints such as nausea, vomiting, abdominal distension, early satiety and anorexia. The aim of the present study was to define the prevalence of dyspeptic complaints and delayed gastric emptying in CRF patients. MATERIAL AND METHODS: Dyspeptic complaints were assessed anamnestically in 62 non-dialyzed CRF patients. Gastric emptying for solids was evaluated by the 13C-octanoic acid breath test in the same population. The CRF patients were compared to 27 healthy volunteers. RESULTS: There was a high prevalence (48%) of dysmotility-like dyspepsia in the investigated population. The gastric emptying rates of CRF patients and healthy volunteers were significantly different (median gastric emptying t(1/2) 83 min versus 60 min, p < 0.01). Diabetic CRF patients had lower gastric emptying rates than non-diabetic CRF patients (median gastric emptying time t(1/2) 113 min versus 77 min, p < 0.01). Even the non-diabetic CRF patients had a significantly delayed gastric emptying rate compared to the healthy volunteers (77 min versus 60 min, p < 0.05). CONCLUSION: It is concluded that dysmotility-like dyspeptic complaints and delayed gastric emptying are highly prevalent in CRF patients.

Blue native polyacrylamide gel electrophoresis: a powerful tool in diagnosis of oxidative phosphorylation defects.

Catalytic activity of oxidative phosphorylation complexes is maintained following separation by Blue Native polyacrylamide gel electrophoresis (BN-PAGE). In BN-PAGE gels, using histochemical staining methods, we have demonstrated enzymatic activity of the complexes I, II, IV, and V in heart and skeletal muscle, liver, and cultured skin fibroblasts. The combination of BN-PAGE and catalytic staining can be successfully applied for detection of complex deficiencies. Tissues from 18 patients with deficiency in the oxidative phosphorylation as detected by spectrophotometric assay were used (10 patients complex IV, three patients complex I, one patient complex II, one patient complex I+III, three patients complex I+IV). The gene defect was located in nuclear DNA in five patients and mitochondrial DNA in one patient. In samples from patients with a severe deficiency, almost complete absence of the corresponding enzyme band is observed after catalytic staining in the gel. In patients with known partial deficiency, a milder decrease of the corresponding enzyme band is demonstrated. The amount of protein in complexes I, V, and III can easily be evaluated in samples from heart and skeletal muscle after separation by BN-PAGE using silver or Coomassie staining. The protein amount in complex IV is difficult to visualize by silver staining but easier by the Coomassie technique. In samples from liver and cultured skin fibroblasts, evaluation of protein amount is more difficult due to high background staining. In these tissues, immunoblotting can be done after BN-PAGE and subsequent transfer to a nitrocellulose membrane.

The Marmara earthquake: epidemiological analysis of the victims with nephrological problems.

BACKGROUND: Crush syndrome resulting from earthquakes is a major cause of morbidity and mortality, as seen during the catastrophic Marmara earthquake that struck Northwestern Turkey in August 1999. This report analyzes the epidemiological characteristics of the crush syndrome victims of this disaster. METHODS: In order to analyze the nephrological problems caused by this earthquake, questionnaires were prepared within the first week of the disaster and sent to 35 reference hospitals that treated the victims. Data obtained by these questionnaires are the subject of this report. RESULTS: Of the 5302 hospitalized patients in reference hospitals, 639 (12.0%) suffered from nephrological problems, and 477 (9.0%) needed dialysis support. Considering the patients with renal problems, there was not any significant difference in gender; however, the incidence of children younger than 10 years and the older population (older than 60 years of age) was significantly lower as compared with the resident population of the affected area (P < 0.001). Nonsurvivors were older (34.5 +/- 16.1 years) than survivors (31.2 +/- 14.4 years, P = 0.048), while no deaths were recorded under the age of 10. Most patients (70.1%) were admitted within the first three days after the earthquake, and the mortality rate among these victims was higher (17.7%) as compared with victims admitted thereafter (10.0%, P = 0.016). The average time period under the rubble was 11.7 +/- 14.3 hours, which was not significantly different between survivors and nonsurvivors, while the victims who required dialysis support spent shorter durations under the rubble, as compared with the ones who were not dialyzed at all (10.3 +/- 9.5 vs. 15.9 +/- 23.1 hours, P < 0.001). CONCLUSION: Victims of catastrophic earthquakes are characterized by a high incidence of renal problems and the need for dialysis support. The incidence of nephrological problems is lower in children, while the period of time under the rubble is not a prognostic indicator of survival.

Delayed gastric emptying in dyspeptic chronic hemodialysis patients.

Hemodialysis patients frequently experience such dyspeptic symptoms as nausea, vomiting, abdominal distension, early satiety, and anorexia. Gastroparesis might be a cause of malnutrition, and parameters of gastric emptying are inversely correlated with serum albumin levels. The aim of the present study is to determine whether delayed gastric emptying is related to dyspeptic symptoms. In 54 hemodialysis patients, a standardized history for dyspeptic symptoms was taken. In addition, gastric emptying for solids was measured in 26 patients, using the (13)C-octanoic acid breath test. There was a high prevalence of dysmotility-like dyspepsia in the hemodialyzed population. A significant difference in gastric emptying between dyspeptic hemodialysis patients and healthy volunteers and between dyspeptic and nondyspeptic hemodialysis patients was shown. There was a significant correlation between gastric emptying and dysmotility-like dyspepsia. Serum albumin level inversely correlated with gastric emptying. In conclusion, there is a high prevalence of dysmotility-like dyspepsia in hemodialysis patients. Dyspeptic patients have significantly delayed gastric emptying compared with both healthy volunteers and nondyspeptic patients.

Continuous ambulatory peritoneal dialysis peritonitis due to Enterococcus cecorum.

Enterococcus cecorum was isolated as the etiologic agent of a continuous ambulatory peritoneal dialysis peritonitis episode in an alcoholic patient. To date, this is only the third infection due to this bacterium, found in the intestinal tract of many domestic animals, that has been reported in humans.

A single center's clinical experience with quadruple immunosuppression including ATG or IL2 antibodies and mycophenolate mofetil in simultaneous pancreas-kidney transplants.

UNLABELLED: Acute rejection remains a major problem in simultaneous pancreas-kidney (SPK) transplant and occurs in 60-100% of the cases. With the introduction of mycophenolate mofetil (MMF) replacing azathioprine (AZA) as a basis immunosuppressant, reduced rates of rejection have been reported. This study investigates the frequency and clinical relevance of allograft rejection in SPK patients receiving antithymocyte globulin (ATG) or Basiliximab induction therapy and cyclosporine Neoral (CyA), MMF, steroid basis immunosuppression. Between December 1996 and October 1999, 21 consecutive patients (15 males, 6 females) received a SPK transplant at our institution with a mean +/- standard deviation (SD) age of 42 +/- 6 yr. Of these, 14 patients were treated with anti-thymocyte globulin (ATG) Fresenius (rabbit) 3-5 mg/kg for 6 +/- 2 d, cyclosporine Neoral (CyA) (trough levels 350-400 ng/mL), MMF 3 g/d and low dose steroid therapy. Seven SPK patients were treated with Basiliximab (Simulect, Novartis 20 mg on d 0 and d 4 post-transplant) instead of ATG. The patients had an average human leucocyte antigen (HLA) mismatch of 3.9/6 and a negative cross match. All patients remained on triple drug therapy. Three patients were switched to tacrolimus instead of Neoral for CyA intolerance. The mean +/- SD cold ischemia time (CIT) of the organs was 10.1 +/- 2.4 h for the pancreas and 10.5 +/- 2.6 h for the kidney. RESULTS: Biopsy-proven rejection occurred in the kidney of 1 ATG patient (8%), which responded to steroid bolus therapy. One of the patients (14%) with Basiliximab induction developed renal allograft rejection, which was resolved after a 6-d course of anti-CD3 mAb (OKT3) treatment. All patients (100%) were free from rejection in the pancreas, as measured by urine amylase levels and glycemic control without the need for exogenous insulin with a mean glycosylated hemoglobin (HBA1C) of 5.1 +/- 0.7%, and serum creatinine with a mean of 1.24 +/- 0.24 mg/dL in a mean follow-up period of 17 +/- 15 months (median 12, range 2 37). CONCLUSION: Triple drug immunosuppression including cyclosporine, MMF and low dose steroids with ATG or interleukin 2 (IL2) receptor antibodies induction therapy appears to be a very suitable immunosuppressive regimen for combined pancreas-kidney transplant (PKT) with a marked reduction in the incidence of rejection.

Significance of qualitative polymerase chain reaction combined with quantitation of viral load in the diagnosis and follow-up of cytomegalovirus infection after solid-organ transplantation.

Quantitative PCR was evaluated in the monitoring of patients with ongoing posttransplantation cytomegalovirus (CMV) infection and antiviral therapy, compared to leukoDNAemia and serology. From January 1998 until May 1999, 61 patients were followed up weekly during 3 months after transplantation by a qualitative PCR. The quantitative PCR was performed on plasma samples from 21 selected patients, of whom 12 had a primary infection and 9 a reactivation or reinfection. Analysis of the viral load differences showed that the viral loads in patients with a primary infection were significantly higher than viral loads in patients with a reactivation (p < 0.01). Based on the results of our study, we can state that qualitative PCR is a good marker for initiating preemptive therapy. In addition, viral quantitation is clinically useful for accurate diagnosis of established CMV disease, and monitoring of antiviral therapy.

Polyarteritis nodosa and the antiphospholipid syndrome.

We report a case of biopsy-proven polyarteritis nodosa (classic type in association with the antiphospholipid syndrome. Medium-sized arteriopathy was confirmed on visceral angiography. Elevated anticardiolipin antibodies were detected before initiating therapy with methylprednisolone and IV pulse cyclophosphamide. Rapid subsidence of symptoms correlated with a gradual normalisation of the erythrocyte sedimentation rate. After 6 months of therapy anticardiolipin antibodies were within normal limits. Only one similar case has been reported so far.

Immunomodulating effects of antibiotics: literature review.

Antibiotics can interact directly with the immune system. This is a review of the immunomodulating effects of antibiotics. The Medline database on CD-ROM was searched for the years 1987 to 1994 using the following search string: "thesaurus explode antibiotics/all AND (thesaurus explode immune-system/drug effects OR thesaurus immune-tolerance/drug effects)." Aspects of the immune system studied were aspects of phagocyte functions: phagocytosis and killing, and chemotaxis and aspects of lymphocyte functions: lymphocyte proliferation, cytokine production, antibody production, delayed hypersensitivity and natural killer-cell activity. In order to quantify and to compare immunomodulatory properties of antibiotics we calculated an "immune index," defined as: number of positive statements--number of negative statements/total number of statements. Concerning phagocytosis, positive effects were observed for cefodizime, imipenem, cefoxitin, amphotericin B and clindamycin and negative effects for erythromycin, roxithromycin, cefotaxime, tetracycline, ampicillin and gentamicin. Clindamycin, cefoxition and imipenem induce enhancement of chemotaxis, whereas cefotazime, rifampicin and teicoplanin decrease chemotaxis. Regarding lymphocyte proliferation, cefodizime has the strongest stimulating effect, whereas tetracycline has the strongest negative effect. Except for erythromycin and amphotericin B the number of statements reported is too small to be conclusive for the interpretation of effects on cytokine production. Erythromycin and amphotericin B appear to stimulate cytokine production. As to antibody production, cefodizime has the strongest positive effect, whereas josamycin, rifampicin and tetracycline have marked negative effects. For delayed hypersensitivity and the natural killer-cell activity the number of statements is too small for any single antibiotic to be conclusive. There are three markedly immuno-enhancing antibiotics (imipenem, cefodizime and clindamycin) and eight markedly immuno-depressing antibiotics (erythromycin, roxithromycin, cefotaxime, tetracycline, rifampicin, gentamicin, teicoplanin and ampicillin).