Hjalmar B. Steinhauer

Effect of prostaglandins D2, E2 and F2α on catecholamine release from slices of rat and rabbit brain

Slices of rabbit or rat brain cortex were preincubated with [3H]noradrenaline, and slices of rabbit caudate nucleus or rat stratum with [3H]dopamine. The slices were then superfused and stimulated electrically. In rat cortex slices, PGE2 (0.01-1 millimicronmol/l) markedly reduced the stimulation-evoked overflow of tritium. PGF2alpha (1 millimicronmol/l) caused a slight decrease only after the formation of endogenous prostaglandins had been blocked by indomethacin. PGD2 (1 millimicronmol/l) had no effect. In slices of rabbit cortex and caudate nucleus as well as in rat striatal slices, none of the prostaglandins (1 millimicronmol/l) caused any change, irrespective of whether the production of endogenous prostaglandins was intact or blocked. The results show that, of three major prostaglandins that occur in the brain, only PGE2 is a potent presynaptic inhibitor of noradrenaline release in the rat. The catecholamine neurones of rabbit brain, and the dopamine neurones of rat striatum, are resistant to these prostaglandins.

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.

Increased Dialysis Efficiency in Tidal Peritoneal Dialysis Compared to Intermittent Peritoneal Dialysis

Hjalmar B. Steinhauer, MD, Medizinische Universitätsklinik, Abteilung Nephrologie, Hugstetterstr. 55, D-W-7800 Freiburg (FRG) Dear Sir, Intermittent peritoneal dialysis (IPD) is considered superior to hemodialysis in elderly patients with advanced cardiovascular diseases and diabetics with active retinopathy [1]. The main disadvantages of IPD are poor dialysis clearances and inadequate sodium balance resulting in poor blood pressure control and increased mortality on long-term treatment [2, 3]. The technique of IPD comprises three distinctive periods – influx of dialysis solution, dwell and outflow of dialysate and ultrafil-trate. During dialysate outflow and before the next inflow is completed, dialysis is diminished or completely interrupted. To enhance dialysis efficiency, a modified IPD was created in which a constant reserve volume of dialysis fluid remains in the peritoneal cavity on top of which a tidal volume of dialysis solution is exchanged (tidal peritoneal dialysis; TPD) [4, 5]. In the present study, dialysis efficiency and peritoneal protein loss in TPD were investigated in comparison to conventional IPD. The protocol was designed as a sequential crossover study. Six patients (female 5, male 1) with end-stage renal failure undergoing IPD for a mean of 9 months (range 2–13) took part in the study. All patients were treated with IPD and TPD consecutively 7 times each. Mean dialysate volume (23 liters), dialysis time (7.5 h), dialysate glucose concentration and total filling volume per cycle (1.5 or 2.0 liters) were identical in both forms of peritoneal dialysis. The tidal volume was chosen to be 50% of the total filling volume. Peritoneal clearances in IPD and TPD were calculated by the equation: r, VxD U”TxP’ Table 1. Peritoneal clearances (ml/min/1.73 m2) and ultrafiltration (ml/min) in IPD and TPD, 7.5 h each Creatinine Urea Phosphate Potassium UF IPD 14.3 17.8 8.45 17.9 3.92 ± 2.0 ± 1.9 ± 0.99 ± 1.7 ± 0.80 TPD 15.2 19.5 10.50 18.5 4.73 ± 1.7 ± 3.2 ± 1.29* ± 3.0 ± 0.92** Results are expressed as means ± SEM. UF= Ultrafiltration. *p < 0.05; **p < 0.01 vs. IPD (Wilcoxon rank sum test).

Increased Ultrafiltration after Erythropoietin-Induced Correction of Renal Anemia in Patients on Continuous Ambulatory Peritoneal Dialysis

Dr. Hjalmar B. Steinhauer, Medizinische Universitätsklinik, Abteilung Nephrologie, Hugstetter Strasse 55, D-7800 Freiburg, (FRG) Dear Sir, Recombinant human erythropoietin (rHuEPO) has been shown to be effective in correcting renal anemia of patients with chronic renal failure undergoing hemodial-ysis [1–4]. Despite that anemia is usually less severe in patients on continuous ambulatory peritoneal dialysis (CAPD) compared to hemodialysis, the correction of anemia will improve the clinical condition of CAPD patients. In order to study the effect of rHuEPO on anemia and peritoneal dialysis efficiency, 8 CAPD patients (agend 26–67 years) were treated with rHuEPO (Cilag Ltd., Schaffhausen, Switzerland) subcutaneously twice weekly with an initial dose of 50 U/kg body weight. Every 4 weeks the rHuEPO dose was increased for 25 U/kg body weight till the target hematocrit (HKT) of 35% had been achieved. In case this HKT was exceeded, rHuEPO was reduced by 25 U/kg body weight. CAPD study exchanges with 4 h dwell time were performed twice weekly in the morning with 1.5 liters 1.5% dextrose monohydrate (Fresenius AG, Bad Homburg, FRG; Baxter, Deerfield, Ill., USA). Subcutaneous administration of rHuEPO was tolerated without severe side effects (short-lasting local pain after subcutaneous injection in 4 patients, increased anti-hypertensive treatment in 2 patients, transient flu-like syndrome in 1 patient). The result are summarized in table 1. RHuEPO-induced correction of anemia was associated with increased peritoneal ultrafiltration (UF). UF/4 h dwell time rose from 156 ± 105 to 264 ± 138 ml after 12 weeks of rHuEPO treatment. Urea clearance increased from 5.5 ± 0.8 to 6.3 ± 1.5 ml/min/1.73 m2. Since urea serum and dialysate concentrations remained unchanged, the augmented clearance of urea is due to the rise in UF. Increased peritoneal UF can be achieved by (1) augmented mesenteric blood flow, (2) rised peritoneal permeability, (3) decreased lymphatic absorption from the abdominal cavity, and (4) increased osmotic gradient between dialysis solution and plasma [5,6]. RHuEPO-induced correction of anemia may rise mesenteric perfu-sion by improved cardiac function [7,8]. A corresponding observation was described in CAPD patients with congestive heart disease after effective digitalis therapy [9]. No data are available on the effect of anemia correction on peritoneal transport, peritoneal lymphatic absorption and osmotic gradient.

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

Abstract. 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 < 0±03), haematocrit rose from 22±8 ± 1±2 to 30±3 ± 1±7% (P < 0±01). A consistent decrease in ferritin concentration was observed during this time (P < 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.

Effects of Long-Term Treatment with Human Recombinant Erythropoietin in Patients on CAPD

Anemia is a common feature in patients with chronic renal failure on regular dialysis treatment. The inappropriate low level of serum erythropoietin is known to be the major cause of anemia in these patients1. The development of recombinant human erythropoietin (rHuEPO) offers for the first time the possibility of an effective and continuous correction of renal anemia2 , 3 . In recent publications several authors described an increase of hematocrit in patients undergoing regular hemodialysis during treatment with rHuEPO2–7. In the initial trials rHuEPO treatment was associated with various adverse effects such as hypertension, convulsions, fistula clotting, and increased serum creatinine, urea, and potassium 2–4.

Effect of L-histidine in vivo on human platelet function and arachidonic acid metabolism

The effect of the amino acid l-histidine on human platelet function and arachidonic acid metabolism was studied in 18 healthy subjects with increased spontaneous platelet aggregation. The participants received placebo or l-histidine 3g/day for 7 days. The intake of l-histidine reduced the degree of spontaneous platelet aggregation (p less than 0.05) and inhibited the generation of platelet TXB2 by 47% (p less than 0.001) whereas platelet PGE2 synthesis was not affected. The mean l-histidine plasma concentration increased from 83.1 +/- 2.4 to 108 +/- 8.1 mumol/l (p less than 0.01) during the study. L-histidine was found to be an effective inhibitor of spontaneous platelet aggregation and platelet TXB2 generation. The present data verify interactions of histidine with human platelet function, probably mediated by arachidonic acid metabolites.