H. G. Sieberth

Pharmacokinetics and pharmacodynamics of cisapride in patients undergoing hemodialysis

Twenty‐two patients who were receiving hemodialysis were studied in three groups of eight subjects each to assess the pharmacokinetics during the dialysis‐free interval and during hemodialysis treatment and to assess the pharmacodynamics of cisapride. Cisapride and its metabolite norcisapride were measured by use of HPLC and gas chromatography, respectively. The pharmacodynamic effect of cisapride was measured by means of radionuclide gastric emptying. After a single oral dose of 20 mg the terminal half‐life of cisapride was 9.6 ± 3.3 hours, the volume of distribution was 4.8 ± 3.3 L/kg, the total oral plasma clearance was 380 ± 161 ml/min, the area under the curve was 1024 ± 447 ng · hr/ml (mean ± SD). Norcisapride only could be detected in the dialysate (0.36 ± 0.067 mg) and was eliminated by a hemodialysis clearance of 34.7 ± 7.9 ml/min. Cisapride reduced gastric retention from 77.6% ± 21.1% to 43.7% ± 18.2% of maximum filling (40 minutes after meals) and normalized the abnormal gastric emptying time in patients receiving dialysis. Cisapride dosage adjustment or substitution after hemodialysis is not necessary.

Use of a cutting balloon for dilatation of a resistant venous stenosis of a hemodialysis fistula.

In a 71-year-old patient with a Brescia-Cimino hemodialysis fistula, high-pressure balloon dilatation failed to open the stenosis completely and a constant waist of the balloon was found. The use of a 3.5-mm coronary cutting balloon (Barath balloon) was helpful in preparing the stenosis for subsequent successful dilatation.

Follow-up results after stent placement in failing arteriovenous shunts: A three-year experience

Self-expandable endoprostheses were used in 18 failing arteriovenous shunts after unsuccessful balloon dilatation. Technical success was satisfactory with an early patency in 17 of 18 shunts. Thrombosis right after stenting occurred in three shunts but was successfully treated in two. Followup history revealed recurrent events of reobstruction due either to stent or shunt stenoses or thrombosis. Restenosis within the stented segment was responsible for reobstruction in about half the cases. Although patency was low with 27% at 18-month follow-up, repeated intervention established a shunt survival rate of 77% at 18-month follow-up. Stent placement in AV shunts is useful for overcoming acute problems of balloon dilatation but does not prevent restenosis.

Increased activity of the autonomic nervous system and increased sensitivity to angiotensin II infusion after therapy with recombinant human erythropoietin.

Bernhard Heintz, MD, Department of Internal Medicine II, RWTH Aachen, Pauwelsstreet 30, D-5100 Aachen (FRG) Dear Sir, The pathophysiological role of the autonomic nervous system in the development of arterial hypertension during regular therapy with recombinant human erythropoietin (rh-EPO) is unclear [1]. Recently, Fritschka et al. [2] reported elevated plasma norepinephrine concentrations and a decrease of < 3⁄4-adrenoreceptors in dialysis patients treated with rh-EPO. Blood samples were drawn from 11 haemodialysis patients at rest and at the peak of physical exercise (initially 25 W, increased by 25 W every 2 min) to determine epinephrine (E), norepinephrine (NE), aldosterone (ALD) concentrations and plasma renin activity (PRA) before and after 6 weeks and 3 months of rh-EPO treatment. An initial dose of 40 IU/kg body weight 3 times per week intravenously was administered. If a haematocrit of 35% was not reached after 4 weeks the dose was increased by 40 IU/kg body weight. If the haematocrit exceeded 35% the dose was reduced by 40 IU/kg body weight or the infusion was completely stopped. Before, after 6 weeks and 3 months after rh-EPO administration an angiotensin II infusion test was performed (initial dose 0.5 μg/min with stepwise increase of 0.5 μg/min until the mean arterial pressure showed an increase of 20 mm Hg). Cardiac output (technetium ven-triculography) was measured and total peripheral resistance (TPR) calculated from mean arterial blood pressure as well (table 1). Resting blood pressure values did not change during the course of rh-EPO therapy. Aldosterone and renin activity also remained unchanged, but epinephrine and particularly norepinephrine increased during rh-EPO therapy, with a peak at 6 weeks of treatment. Exercise caused the systolic blood pressure to increase before and

Magnesium pyridoxal 5-phosphate glutamate reduces hyperlipidaemia in patients with chronic renal insufficiency

SummaryChronic renal insufficiency is often accompanied by hyperlipidaemia and subsequent coronary heart disease.Two groups of 15 patients with serum creatinine >2 mg/100 ml and serum cholesterol >250 mg/100 ml were given 3×50 mg magnesium pyridoxal 5-phosphate glutamate (MPPG) or placebo for 12 weeks in a double-blind, randomised study.Total cholesterol in the MPPG group (282.4 mg·100 ml−1) was lower than in the placebo group (354.3 mg·100 ml−1) after 12 weeks of treatment. Triglycerides in the MPPG group were 265.1 mg·100 ml−1 compared to 361.9 mg·100 ml−1. After 12 weeks on MPPG the LDL/HDL ratio of 3.56 was lower than in the placebo group — 6.83. Side effects in the MPPG group were similar to those in the placebo group. Thus, MPPG was an effective antihyperlipidaemic agent in patients with renal insufficiency.

Decreased glomerular basement membrane heparan sulfate proteoglycan in essential hypertension

Abstract Heparan sulfate proteoglycans are major components of the glomerular basement membrane and play a key role in the molecular organization and function of the basement membrane. Moreover, their presence is essential for maintenance of the selective permeability of the glomerular basement membrane. Recently, we isolated and characterized a novel small basement membrane–associated heparan sulfate proteoglycan from human aorta and kidney. Partial amino acid sequence data clearly show that this heparan sulfate proteoglycan is distinct from the large basement membrane–associated heparan sulfate proteoglycan (perlecan). Using specific monoclonal antibodies, we have shown that the novel heparan sulfate proteoglycan is located predominantly in the glomerular basement membrane and, to a lesser extent, in the basement membrane of tubuli. Turnover or, in the course of kidney diseases, degradation of heparan sulfate proteoglycan from glomerular basement membranes may lead to urinary excretion of heparan sulfate proteoglycan, which can be measured by a sensitive enzyme immunoassay. The aim of the present study was to analyze whether changes in the structure and function of glomerular basement membranes can be directly detected by measurement of the excretion of a component of this basement membrane, eg, heparan sulfate proteoglycan into urine. The excretion of this small heparan sulfate proteoglycan was compared after physical exercise in normotensive and hypertensive subjects. Normotensive subjects and treated, essential hypertensive patients underwent a standardized workload on a bicycle ergometer. Biochemical characterization of the urinary proteins and heparan sulfate proteoglycan was performed before and 15 and 45 minutes after exercise. In both groups, physical exercise induced a significant increase in the excretion of urinary α1 microglobulin and albumin. However, a 10-fold increase in the urinary excretion rate of heparan sulfate proteoglycan was seen in normotensive subjects under exercise. In hypertensive patients, the relative increase in heparan sulfate proteoglycan excretion was significantly diminished ( P <.05). These data, supported by immunohistochemistry, indicate changes in the glomerular basement membrane of the kidney in hypertension. Therefore, determination of urinary excretion of this novel small heparan sulfate proteoglycan after exercise may be a sensitive marker for the detection of basement membrane alterations in hypertension.

Technical aspects and results of percutaneous transluminal angioplasty in Brescia-Cimino dialysis fistulas

Our experience with percutaneous transluminal angioplasty for treatment of stenoses and occlusions in surgically created arteriovenous fistulas (Brescia-Cimino) is reported. Methodological aspects are emphasized. Forty-nine PTAs were performed in 36 patients, in 3 combined with the use of a vascular metallic endoprosthesis (Wallstent). The initial success rates for stenoses and occlusions and occlusions were 91% and 77%, respectively. Long stenoses and occlusions (>4 cm) showed significantly worse initial results (55%) as compared to short ones (95%). Of the primarily successfully treated shunts, 90% are still functioning after a mean follow-up time of 8 months. The results indicate that PTA may replace surgical intervention as the primary method for treatment of insufficient flow for internal arteriovenous shunts, provided fresh thrombi are not the cause of the occlusion. Metallic endoprostheses and the use of atherectomy catheters were shown to be a valuable adjunct to classical PTA in selected cases.

Response of Vasoactive Substances to Intermittent Ultrafiltration in Normotensive Hemodialysis Patients

The changes in blood volume (BV), atrial natriuretic peptide (ANP), plasma renin activity (PRA), aldosterone (Aldo), norepinephrine (NE), epinephrine (Epi), parathyroid hormone (PTH), arginine vasopressin (AVP) and the cyclic nucleotides cAMP and cGMP were measured during a fluctuating BV cycle in 15 patients with end-stage renal failure maintained on chronic hemodialysis (HD). HD consisted of 4 periods of about 60 min each. The first half of each HD period consisted of ultrafiltration (UF) greater than 1,000 ml/h, and the second half consisted of no UF. Changes in relative BV were measured using continuous hemoglobinometry. Total BV at the end of treatment was 74.3 +/- 6.9% of the pretreatment volume. A significant positive correlation between BV and the levels of ANP, PTH, Epi and cGMP and an inverse correlation between BV and PRA, Aldo, AVP and NE were demonstrated. While mean values of NE and AVP levels were directly related to actual changes in BV, individual values did not homogeneously reflect this relationship. The cyclic nucleotides cGMP and cAMP did not follow immediate BV changes, but showed a significant decrease correlated with diminished BV. Based on a pre-postdialysis analysis, significant changes in PRA and Aldo were missing. It seems possible that vascular stability in dialysis patients may be maintained by the response of NE and AVP, and not by the renin-aldosterone system. The changes in ANP and cGMP values correlated most significantly (r = 0.38 and r = 0.51, p < 0.005) with the changes in BV, but no single variable could explain the blood pressure regulation during HD with intermittent rapid UF.

Influence of oral contraceptive agents on kidney function and protein metabolism

SummaryThe present study was an investigation of the effect of oral contraceptives on kidney function as well as a brief examination of protein metabolism, since glomerular filtration rate depends to a large extent on daily protein intake. 28 healthy women not taking contraceptives and 46 healthy women (aged 20–28 y) on one of three different types of oral contraceptive (combination preparations) were investigated [Minulet®/Femovano®, Marvelon®, Diane®].In all groups on oral contraceptives the endogenous creatinine clearance was significantly increased. The potassium excretion rate was significantly elevated in the groups taking Marvelon® and Diane®, and the sodium excretion rate was significantly increased in those on Minulet®/Femovan® and Diane®.In all groups on contraceptives the albumin excretion rate was numerically but not significantly elevated. No significant differences were found in the daily oral protein intake or the nitrogen excretion rate on comparing the groups taking contraceptives with the control group. However, the ratio nitrogen excretion rate/daily protein intake was significantly increased in those on Minulet®/Femovan® and Diane®. The study has shown that besides their various effects on renal tubular function, oral contraceptives are able to increase the glomerular filtration rate, and certain types have a protein catabolic effect.

EFFECT OF LACTATE ON THE ABSORPTION AND RETENTION OF ALUMINUM IN THE REMNANT KIDNEY RAT MODEL

In previous investigations we found the gastrointestinal absorption of aluminum (Al) to be enhanced in uremic rats and this phenomenon could not be attributed to either calcitriol deficiency or secondary hyperparathyroidism. The purpose of this study was to examine whether carboxyl ligands such as lactate could affect the absorption of A1 in our model and, if so, whether this would impose additional alterations on the A1 absorption in uremia. Uremic rats and controls were studied with single oral loads of either A1 chloride or A1 lactate and, subsequently, urinary A1 excretion was measured for 5 days. Compared with Al chloride, administration of A1 lactate resulted in significantly higher urinary excretion rates of A1 in uremic rats (55.5 +/- 22.7 vs. 27.4 +/- 7.0 micrograms; 2.06 +/- 0.84 vs. 1.01 +/- 0.26 mumol) and in controls (23.6 +/- 8.5 vs. 11.9 +/- 4.3 micrograms; 0.87 +/- 0.31 vs. 0.44 +/- 0.16 mumol). However, with either A1 load the recovery of A1 from urine was substantially higher in uremic animals. In contrast, only in controls was there a more pronounced rise in serum A1 concentrations following ingestion of A1 lactate, whereas in uremic rats this increase had a similar magnitude following A1 chloride and A1 lactate, suggesting a larger apparent volume of distribution of the latter. Adjustment of the pH of the A1 lactate-containing solution to 7.0 or oral administration of sodium lactate together with A1 chloride yielded essentially similar results. These observations indicate that the enhanced intestinal absorption of A1 in uremia is further augmented by lactate regardless of the mixture of hydroxolactato complexes employed.(ABSTRACT TRUNCATED AT 250 WORDS)