[High-dose chemotherapy with transplantation of autologous stem cells in advanced germ-cell poor-risk testicular tumors].

Testicular tumors illustrate curable cancer, but 25% patients are resistant to standard therapy. High-dose chemotherapy (HDC) is promising therapy for germ-cell tumors with poor prognosis. HDC and transplantation of autologous stem cells were performed in 13 patients with germ-cell testicular tumors (GTT). In 6 patients of group 1 HDC was first-line treatment in poor prognosis, in 7 patients (group 2) it was a salvage treatment after recurrences. Patients of group 1 had longer mean survival than those of group 2 (31.3 and 11 months, respectively; p = 0.136). Two patients died of HDC complications. Neurological, hematological and other complications occurred. In spite of 50-90% remission after HDC, multicenter prospective randomized trials will give final conclusion on effectiveness of HDC which must be performed in special clinics having many specialists in their staff (urologists, oncologists, chemotherapists, etc.).

A simultaneous study of the metabolism of apolipoprotein B and albumin in nephrotic patients.

BACKGROUND: The nephrotic syndrome is characterized by proteinuria, hypoalbuminemia and hyperlipidemia. Despite intensive research it is not clear at present what the causal links are between these pathological findings. METHODS: Stable isotope labeled amino acid tracer kinetic analysis was used to simultaneously investigate the metabolism of four apolipoprotein B-containing lipoproteins (VLDL1, VLDL2, IDL and LDL) and albumin in seven patients with nephrotic syndrome and marked hypercholesterolemia, in two additional nephrotic patients with concomitant renal failure and mixed hyperlipidemia, and in a matched group of normolipidemic controls. RESULTS: Increased concentrations of VLDL2, IDL and LDL were due to (a) impaired VLDL2 and IDL delipidation, (b) reduced LDL catabolism, and (c) a trend towards an increased rate of total apolipoprotein B production. The rate of fractional albumin elimination was three times higher in patients than in controls and the rate of albumin synthesis was increased by 45%. No correlations were detectable between rates of apolipoprotein B production and the rate of albumin synthesis. CONCLUSIONS: The results of this study suggest that hyperlipidemia in nephrotic syndrome is predominantly the result of delayed lipoprotein delipidation and catabolism. There is no evidence that it is driven by a general increase of the rate of hepatic protein synthesis.

Effect of a silver device in preventing catheter-related infections in peritoneal dialysis patients: silver ring prophylaxis at the catheter exit study.

Catheter-related infections remain a significant cause of method failure in chronic peritoneal dialysis (PD) therapy. Given the increasing antibiotic resistance, such nonpharmacological strategies as local silver devices attract more interest. To establish whether a silver ring device (designed by Grosse-Siestrup in 1992) mounted onto the PD catheter and placed at the exit site at skin level is effective in preventing exit-site and other catheter-related infections, a prospective 12-month, multicenter, controlled study stratified by diabetes status was conducted. The study subjects were assessed by an extensive structured inventory, including a broad spectrum of control variables, such as age, body mass index (BMI), Staphylococcus aureus carrier status, catheter features, mode and quality of PD therapy, comorbidity, and psychosocial rehabilitation. Ten experienced German outpatient dialysis centers (seven adult, three pediatric) participated in the trial. All eligible patients (n=195) from the study area without catheter-related infections during the ascertainment period were included (incidental subjects undergoing PD therapy for at least 3 months). The main outcome measures were the occurrence of first exit-site infections (primary study end point), sinus tract/tunnel infection, and peritonitis. Ninety-seven patients were assigned to the silver ring and 98 patients to the control group. Baseline characteristics of age, sex, proportion of pediatric and incidental patients, S aureus carrier status, and other variables were similar in both groups. The incidence of infections in the silver ring group versus the control group was as follows: 23 of 97 versus 16 of 98 patients had exit-site infections, 12 of 97 versus 12 of 98 patients had sinus tract/tunnel infections, 16 of 97 versus 18 of 98 patients had peritonitis, respectively. Kaplan-Meier analysis for the probability of an infection-free interval showed no statistical difference (log-rank test) between the two groups. Displacement of the silver ring contributed to study termination in 6% of the study group patients, including two patients with catheter loss. Univariate analysis and multiple logistic regression identified younger age (<50 years), low serum albumin level (<35 g/L), number of previously placed PD catheters, short cuff-exit distance (<2 cm), and S aureus nasal carriage as risk factors for the development of exit-site infections. In conclusion, our study does not show any benefit of the silver ring in preventing catheter-related infections in PD patients. Thus, prevention of infection-related method failure in PD still has to rely on conventional antibiotic treatment strategies and less so on alternative methods.

[Comparative study of the pharmacokinetics of amitriptyline oxide and trimipramine after single administration in healthy male probands and patients with renal failure]. / Vergleichende Untersuchung zur Pharmakokinetik von Amitriptylinoxid und Trimipramin nach Einmalgabe bei gesunden männlichen Probanden und Patienten mit Niereninsuffizienz.

The pharmacokinetics of the antidepressants amitriptyline oxide and trimipramine and their major metabolites amitriptyline, nor-triptyline and desmethyltrimipramine, were studied in twelve healthy male subjects (aged from 22 to 62 years) and twelve patients (aged from 25 to 73 years) with severe renal impairment (glomerular filtration rate < 10 ml/min). Oral single doses of 60 mg amitriptyline oxide and 50 mg trimipramine, separated by a washout period, were administered to all study participants. Blood and urine samples were collected up to 120 hours after administration. For trimipramine and desmethyltrimipramine, a new HPLC method was developed. The "Fischer Somatic and Undesired Effects Check List" was used for the assessment of adverse events. The mean plasma half-life and AUC of amitriptyline oxide and its metabolites were significantly higher in patients than in healthy adults. For trimipramine the AUC was significantly higher in patients. The plasma half-life of trimipramine was longer in patients, but statistically not significant. The maximum plasma concentrations for both drugs and metabolites were at an average distinctly higher in patients. Clearance rate of amitroptylinoxide and trimipramine also differed between the two groups. Correlating with these results a high incidence and a longer persistence (in most cases > 12 hours) and more pronounced adverse effects were noted in the patient group, whereas in volunteers adverse events were only observed up to approximately eight hours.

Inhibition of C5a-induced actin polymerization, chemotaxis, and phagocytosis of human polymorphonuclear neutrophils incubated in a glucose-based dialysis solution.

Chemotaxis and phagocytosis are important functions of phagocytic cells, which are closely related to cytoskeletal reorganization. These functions may be abnormal in phagocytes of uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). In order to examine whether these abnormalities result from treatment, we studied actin polymerization (AP), as an index of cytoskeletal alterations, chemotaxis, and phagocytosis in polymorphonuclear neutrophils (PMNs) of healthy subjects. Polymorphonuclear neutrophils were exposed to either a hepes buffer or a glucose-based dialysis solution (GBDS) of different pH's (5.2, 7.4) and different glucose concentrations (1.36%, 2.27%, 3.86%). After incubation for 0, 5, or 20 minutes, cells were activated with 10 nmol/L C5a-complement. AP was measured as filamentous (F) actin content by NBD phallacidin staining and FACS analysis. Chemotaxis of PMNs was measured in Boyden chambers. In addition, phagocytosis of zymosan particles was assessed. Prior exposure to GBDS pH 5.2 of each glucose concentration immediately and completely inhibited AP in response to 10 nmol/L C5a-complement, reduced chemotaxis (> 95%), and completely inhibited phagocytosis. The inhibition was pH-dependent, since GBDS pH 7.4 caused less inhibition of these functions. We conclude that glucose-based dialysis solutions are cytotoxic towards neutrophils and completely inhibit their ability to display responses requiring cytoskeletal reorganization.

Effect of CAPD dialysate on the release of eicosanoids and cytokines from human peritoneal macrophages.

The effect of fresh peritoneal dialysis (PD) solution and effluent on the generation of eicosanoids and cytokines by human peritoneal macrophages (PMO) was studied in vitro. PMO, isolated by density gradient separation from patients undergoing intermittent peritoneal dialysis (IPD), were incubated for 2 h with PD effluent after dwell periods of 5 to 240 min or fresh PD solution. Supplemented RPMI-1640 medium served as control. PMO were stimulated by calcium ionophore A23187 (10 M). PD solution significantly inhibited the release of prostanoids (PGE2, TXB2, 6-k-PGF1), leukotrienes (LTB4, LTC4), and cytokines (11-6, TNF) from PMO by 60 to 96% (p < 0.05). Addition of A23187 increased the generation of TXB2, LTB4, and LTC4 in PD solution adjusted to pH 7.4 to 2.7 up to 28.6 times the basal level, but was ineffective in PD fluid at pH 5.2. Incubation of PMO with PD effluent of varying dwell times resulted in a rise of all assayed mediators (p < 0.05). The release of IL-6 increased continuously from 80 +/- 10 pg/10(6) PMO (0 min dwell time) to 440 +/- 104 pg/10(6) PMO (4 h dwell time, mean +/- S.E.M.). TNF generation rose from 6.0 +/- 0.1 pg/10(6) PMO (0 min dwell time) to 162 +/- 54 pg/10(6) PMO after 5 min dwell time and remained constant with effluents of longer dwell times (15 to 240 min). Exposure of PMO to PD effluents after 240 min dwell time tended to decrease the median levels of PGE2, TXB2, and 6-k-PGF1.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of amino acid based dialysis solution on peritoneal permeability and prostanoid generation in patients undergoing continuous ambulatory peritoneal dialysis.

The acute effect of amino acid based dialysis solution on peritoneal kinetics of amino acids and plasma proteins in comparison to conventional glucose-based dialysate was studied in 9 patients with end-stage renal failure on continuous ambulatory peritoneal dialysis. Instillation of 2.6% amino acid solution resulted in raised plasma concentrations of all essential amino acids included in the dialysis fluid (p less than 0.005). The amino acid solution induced an augmented leakage of plasma proteins into the dialysate at all dwell times investigated (1-8 h). After a dwell time at 8 h, the dialysate total protein increased from 2.62 +/- 0.45 g with glucose dialysate to 3.85 +/- 0.42 g with amino acid solution (p less than 0.05). Corresponding results were obtained for beta 2-microglobulin, albumin, transferrin, IgG, and for the non-essential amino acids alanine, citrulline, and glutamine (p less than 0.025) not included in the initial amino acid composition of the dialysis fluid. During the use of amino acid based dialysis fluid, the effluent prostaglandin E2 concentration increased by more than 80% in comparison to glucose dialysate (p less than 0.025). The augmented loss of proteins induced by the amino acid solution was positively correlated with increased dialysate prostaglandin E2 (r = 0.8894; p less than 0.001). Peritoneal ultrafiltration was not affected by the use of amino acid based dialysate fluid. The present results indicate that amino acid based dialysis fluid enhances the peritoneal permeability for plasma proteins and amino acids, probably mediated by locally generated prostanoids.

Effect of human recombinant erythropoietin on anaemia and dialysis efficiency in patients undergoing continuous ambulatory peritoneal dialysis.

The effect of long-term treatment with human recombinant erythropoietin (rHuEPO) has been studied in nine end-stage renal disease patients on continuous ambulatory peritoneal dialysis (CAPD). RHuEPO was administered subcutaneously twice weekly in rising doses starting with 50 Ukg-1 body weight. After 3 months of rHuEPO haemoglobin increased from 77.7 +/- 3.2 to 112.7 +/- 5.6 g l-1 (P less than 0.03), haematocrit rose from 22.8 +/- 1.2 to 30.3 +/- 1.7% (P less than 0.01). A consistent decrease in ferritin concentration was observed during this time (P less than 0.05). After 12 months of rHuEPO treatment and increased oral iron supplementation the rises of haemoglobin and haematocrit remained stable without other significant haematological changes. The rHuEPO-induced rise in haematocrit was associated with an increased peritoneal ultrafiltration (UF) without change in diuresis and body weight. UF improved from 128 +/- 28 ml 4 h-1 dwell time to 273 +/- 45 ml 4 h-1 (P less than 0.03) within 3 months of rHuEPO treatment, and remained stable during the following study period (month 12: 253 +/- 43 ml 4 h-1, P less than 0.05). The rise in UF resulted in improved peritoneal clearances of creatinine, urea, potassium, and phosphate (P less than 0.05, month 3). No change was observed in serum urea, creatinine, calcium, and potassium. Serum phosphate increased throughout the first 6 months of rHuEPO (P less than 0.05). No severe adverse effects of rHuEPO treatment could be observed. The present results demonstrate that long-term subcutaneous administration of rHuEPO is effective in correcting renal anaemia in CAPD patients and may improve dialysis efficiency by increased peritoneal ultrafiltration.

One year experience with subcutaneous human erythropoietin in CAPD: correction of renal anemia and increased ultrafiltration.

After 6 months of (recombinant human erythropoietin) rHuEPO treatment we recently observed an increased peritoneal ultrafiltration (UF) (Nephron 53: 91, 1989). The aim of the present study was to investigate the long term effect of subcutaneous (SC) on dialysis efficiency in CAPD. Fourteen patients (11 female, 3 male, mean age 42.6, range 18-65 years) with renal anemia (HCT less than 28%) took part in the study. rHuEPO was administered s.c. twice weekly in an initial dose of 50 U/kg body weight. This dose was increased by 25 U/kg body weight every 4 weeks till the target HKT of 35% had been achieved. After 12 months of mean time of treatment (range 8-14 months) hematocrits had increased from 23.3 +/- 3.2 (x +/- SD) to 36.6 +/- 5.3% (p less than 0.005). UF improved from 0.70 +/- 0.22 to 1.03 +/- 0.47 ml/min (4 hr dwell time, 1.5% glucose monohydrate) (p less than 0.03). Increased UF resulted in an augmented creatinine clearance (p less than 0.05). No changes were observed in serum chemistries, body weight, pulse rate or cardiothoracic index. The observed increase in peritoneal ultrafiltration might be due to augmented mesenteric perfusion resulting from improved cardiac function. The sustained increase in UF after rHuEPO-induced correction of renal anemia may improve the fluid balance on CAPD patients.

Pharmacological manipulation of peritoneal transport in CAPD.

Various endogenous compounds and drugs influence different determinants of peritoneal transport. Catecholamines affect vascular diameter and mesenteric blood flow. Several gastrointestinal hormones were found to induce splanchnic vasodilation and to augment the effective vascular surface. Different prostanoids, histamine, and bradykinin influence peritoneal mass transfer by increasing vascular permeability. Vasodilative acting drugs, diuretics and surface active compounds were found to augment peritoneal solute clearances and water efflux by acting on peritoneal vessels or the serosal surface of the peritoneal membrane. Hyperosmolar dialysis solutions increase ultrafiltration and contribute to total peritoneal clearance by convective transport. The present paper aims to summarize the current knowledge on pharmacological and physiological manipulation of peritoneal transport function and to show some ways of its clinical use.