U. Gladziwa

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.

Pharmacokinetic Optimisation of the Treatment of Peptic Ulcer in Patients with Renal Failure

SummaryThe pathogenesis of peptic ulceration is not yet clear. It could be due to an imbalance between acid secretion and mucosal defensive and/or protective mechanisms, but the association between Helicobacter pylori and peptic ulceration has questioned this hypothesis. Therefore, drugs inhibiting acid secretion and/or eradicating H. pylori are of major interest. Peptic ulcer disease is often associated with renal failure. For the selection of the proper dosage of these agents their pharmacokinetic properties and alterations in pharmacokinetics in various disease states, including renal failure, should be known.As histamine H2-receptor antagonists and pirenzepine are mainly eliminated by the renal route their elimination is dependent on creatinine clearance. Consequently, their elimination will be impaired in patients with renal insufficiency, which makes dosage reduction mandatory in these patients. No dosage supplementation is necessary after any type of dialysis because the drugs are removed in insignificant amounts by the various blood purification procedures.Misoprostol and proton pump inhibitors, such as omeprazole, lansoprazole and pantoprazole, are primarily eliminated by nonrenal routes. Therefore no dosage adjustments are necessary in patients with renal insufficiency. Bismuth salts, sucralfate and antacids should be avoided in patients with renal failure because of the accumulation of their cations and the associated risk of toxic reactions.For most agents more long term experience from comparative and double-blinded studies is needed to define better their clinical efficacy and tolerability in patients with renal failure.

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.

Evidence of Hepatitis C Virus Infection in Peritoneal Fluid but Not in Dialysate and Ultrafiltrate or Hemofiltrate

Dr. U. Gladziwa, Department of Internal Medicine II, Technical University of Aachen, Pauwelsstrasse 30, D-52057 Aachen (Germany) Dear Sir, With great interest we read the short communication by Caramelo et al. [1], who found hepatitis C virus (HCV) antibodies in 12 hemodialysis and 5 continuous ambulatory peritoneal dialysis patients. All sera of the studied patients were positive for HCV RNA, whereas polymerase chain reaction (PCR) performed on samples of hemodialysis ultrafiltrate or peritoneal effluent were always negative for HCV RNA. We would like to draw your attention to a multicenter clinical study where we investigated the prevalence of anti-HCV in patients on peritoneal dialysis [2]. The reactive sera were confirmed by RIBA, and viremia was determined by PCR. The total prevalence of anti-HCV among the patients studied was 18 out of 333 (5.4%). The prevalence of anti-HCV among the centers ranged from 0 to 30%. Fifteen out of 18 sera reactive by ELISA were positive when tested by RIBA resulting in a prevalence of 4.5%. These sera were considered as truly positive and tested by PCR for viremia. Eleven of the 15 seropositive patients showed HCV RNA in serum when tested by nested PCR, indicating viremia in most of the antibody-positive patients. From the 11 patients whose sera were positive for HCV RNA, 9 dialysates were tested. Seven of 4 showed antibodies by ELISA or HCV RNA, respectively, also in the peritoneal dialysate. There is no doubt that blood transfusion is a source of HCV infection. However, in our study the total duration of dialysis (peritoneal and hemodialysis duration) was found to be a significant risk factor. This correlation implies nosocomial modes of HCV infection. Caramelo et al. [1] could show that a significant group of patients remained HCV antibody negative, although they shared the same dialysis machine with positive patients. However, whether the sharing of hemodialysis machines contributes to HCV transmission remains moreover to be elucidated. For the first time, we detected the presence of antibodies against various structural and nonstructural antigens (C22, C33c, C100) and HCV RNA in the peritoneal dialysate of seropositive peritoneal dialysis patients. Krautzig et al. [3] found in 4 of 5 HCV-RNApositive patients the peritoneal dialysate also positive, at least on 1 of 3 occasions. The HCV RNA was only in 1 case 3 times positive. It is interesting that HCV RNA was detected in serum and dialysate of our studied patients in 73.3 and 44.4%, respectively. This observation

Gallstone Disease in Dialysis Patients

Dr. U. Gladziwa, Department of Internal Medicine II, Technical University of Aachen, Pauwelsstrasse 30, D-52057 Aachen (Germany) Dear Sir, We read with great interest the short communication by Badalamenti et al. [1], who found a higher prevalence of gallstone disease in patients on regular dialysis treatment (33 of 119; 28%) than in the general Italian population (8-11%). Twenty-nine had gallstones and 4 had had previous cholecystecto-mies for colicky gallstones. This study shows some similarities with the findings of a large clinical study from our nephrology department where we also investigated the prevalence of cholelithiasis in hemodialysis patients [2]. In a retrospective study, 321 consecutive hemodialysis patients admitted to our medical clinic with end-stage renal disease were screened sonographically for the presence of gallstones. An ageand sex-matched control population without evidence of renal disease (normal levels of serum creatinine and urea and inconspicuous findings of the kidneys on sonography) was recruited from 7,000 patients admitted for routine abdominal sonography. The overall prevalence of cholelithiasis in the hemodialysis population was 20.9% (67 of 321, including 25 patients with cholecystectomy; 3 men, 22 women: 18 prior to, 4 after the start of dialysis therapy; men 13.5%, women 30.9%) and 13.4% in the controls (43 of 321; men 10.3%, women 17.6%) (p = 0.0119). However, considering that 10 of the 18 women with previous cholecystectomy had normal renal function, no significant difference could be detected between the patients with renal failure and the controls (p = 0.126). Therefore, despite a higher prevalence of gallstone disease, we could not identify chronic renal failure as a risk factor for gallstones. Similar to the study of Badalamenti et al. [1], our preliminary results failed to show any correlation between the frequency of gallstones and plasma parathyroid hormone (1-84). In contrast to Badalamenti et al. [1], who demonstrated an increase in the prevalence of gallstones with age, we were unable to detect such a relationship when the groups were compared according to decades of life. Our findings are in accordance with those of Pahl et al. [3], who reported that 13% of patients with end-stage renal disease and maintained on hemodialysis were found to have cholelithiasis at autopsy. In addition, another 9% had had previous cholecystectomy, raising the cumulative incidence to 22%. However, necropsy surveys are unsatisfactory because necropsy subjects are not representative of the living population. In conclusion, the findings of our large clinical study argue against an important role of hemodialysis as a risk factor for gallstone disease. Nonetheless, cholelithiasis should be

Fluorid modifiziert die Entstehung der aluminiuminduzierten Osteopathie bei Niereninsuffizienz

Die Akkumulation von Aluminium bei Niereninsuffizienz fuhrt zu einer schweren adynamischen Osteopathie, die histologisch entweder als „Aplastische Osteopathie“oder als „Osteomalazie“imponiert (Ittel 1992). Bei beiden Varianten der Aluminiumosteopathie ist als pathogenetischer Mechanismus eine Reduktion der Zahl aktiver Osteoblasten vorgeschlagen worden (Sedman et al. 1987). Fluorid erhoht uber direkte und indirekte Wirkung die Zahl und Aktivitat der Osteoblasten und zeigt in dieser Beziehung ein dem Aluminium entgegengesetztes Wirkungsprofil (Farley et al. 1983). Die vorliegende Studie untersuchte daher tierexperimentell die Frage, ob durch die Gabe von Fluorid die aluminiuminduzierte Osteoblastensup-pression antagonisiert und hierdurch der schwere Mineralisationsblock uberwunden werden kann. Ferner war von Interesse, inwieweit die Exposition gegenuber Fluorid bei der Entstehung der unterschiedlichen histologischen Subtypen der Aluminiumosteopathie bedeutsam sein konnte, und ob Fluorid die Deposition von Aluminium im Knochen beeinflussen wurde.

Pharmacokinetics of Furosemide in Patients with Chronic Renal Failure

SummaryIn a randomised, crossover trial the pharmacokinetics of furosemide (frusemide) were studied after single intravenous (30-minute infusion of 120mg) and oral (500mg) doses in 10 patients with chronic renal insufficiency (CLCR 16.7 ± 5.5 ml/min). Blood and urine samples were collected over 36 hours. Furosemide was analysed in serum and urine by a specific and sensitive HPLC method. After a lag time of 0.5 ± 0.5 hours (mean ± SD), peak plasma levels of 20.5 ± 12.0 mg/L were reached within 2.1 ± 0.7 hours. The mean plasma t½ of furosemide was 4.6 hours following intravenous administration and 11.8 hours after oral dosing (p = 0.0073). Within 24 hours, 14.9 ± 7.6% (IV) and 9.4 ± 5.5% (oral) of unchanged furosemide was excreted in the urine. The total body clearance was 46.3 ± 14.0 ml/min and the renal clearances amounted to 6.8 ± 3.9 (IV) and 5.5 ± 2.9 (oral) ml/min. The volume of distribution averaged 0.21 ± 0.07 L/kg. The absolute bioavailability of furosemide (67.9 ± 25.3%) was not affected by the chronic renal disease since it was comparable with data found in healthy subjects.

Sekundärer Hyperparathyreoidismus und Sonographie der Epithelkörperchen bei Dialysepatienten

Der sekundare Hyperparathyreoidismus stellt nach wie vor eine der Hauptkomplikationen der chronischen Niereninsuffizienz bei Langzeitdialyse dar. Im Skelett uberwiegt die osteoklastare Resorption den osteoblastaren Neuanbau; es kommt zur Endostfibrose und zum Auftreten von minderwertigem Faserknochen entsprechend einer Ostitis fibrosa. Daneben konnen aber auch Veranderungen der Knochenmasse wie eine Osteosklerose oder Osteopenie auftreten. Die Patienten klagen uber vermehrte Knochenschmerzen.

Aluminiumresorption bei Antacidatherapie mit Magaldrat zur Streßblutungsprophylaxe

Seit der ersten Beschreibung der klinischen Manifestation der Aluminiumtoxizitat bei Patienten mit dialysepflichtiger Niereninsuffizienz in Form der rasch progredienten Encephalopathie [1] haben sich erhebliche Veranderungen in Bezug auf Incidenz und klinische Symptomatik der chronischen Aluminiumtoxizitat ergeben. Neben der typischen Encephalopathie wurden schwere, Vitamin D-resistente Osteomalazien und adynamische Osteopathien und eine mikrozytare Aggravation der renalen Anamie als Folge einer Aluminiumakkumulation beobachtet [4]. Mit Verbesserung der Qualitat des Dialysewassers und Einschrankungen beim Einsatz aluminiumhaltiger Phosphatbinder hat sich das Spektrum aluminiumassoziierter Erkrankungen zu subtileren Manifestationsformen verschoben. So dokumentierten Untersuchungen von Altmann [2] klinisch inapparente Storungen von psychomotorischen Leistungen und andere Autoren registrierten in diesem Zusammenhang eine unspezifisch gesteigerte kardio- und zerebrovaskulare Morbiditat [3]. Neben Patienten mit chronsicher dialysepflichtiger Niereninsuffizienz existieren weitere Risikokollektive, bei denen die Konstellation hochdosierte orale Aluminiumexposition und eingeschrankte exkretorische Nierenfunktion anzutreffen sind. Hierbei sind vor allem kritisch kranke Patienten hervorzuheben, die im Rahmen ihrer intensivmedizinischen Behandlung zur Stresblutungsprophylaxe repetitiv mit aluminiumhaltigen Antazida therapiert werden. Arbeiten von Priebe [7] und anderen Autoren haben die gute Wirksamkeit dieser Therapieschemata dokumentiert. Im Gegensatz zu chronischen Dialysepatienten ist jedoch der Umfang der Aluminiumresorption bei diesen Patienten unzureichend untersucht worden.