G. Schütterle

Analysis of left-ventricular changes associated with chronic hemodialysis: a noninvasive follow-up study

To assess the reasons for the frequent cardiovascular complications in patients with end-stage renal disease (ESRD), 61 out of 131 normotensive ESRD patients originally examined (mean ESRD duration: 71 +/- 41 months) were followed over 2.5 years by echo-, electro- and mechanocardiography. Clinical and biochemical parameters were comparable. The prevalence of pericardial effusion (3%), pericardial thickening (14%), aortic valve sclerosis (14%) and mitral valve anulus sclerosis (12%) was unchanged. The interventricular septum diameter (14.3 +/- 3.0 vs. 16.4 +/- 3.4 mm), index of left-ventricular (LV) wall asymmetry (1.25 +/- 0.30 vs. 1.52 +/- 0.36) and left atrial diameter (38.3 +/- 5.4 vs. 42.6 +/- 3 mm) increased (p less than 0.001). The LV end-systolic diameter decreased slightly (35.8 + 6.3 vs. 34.2 +/- 6.4 mm; p less than 0.05), with no significant changes for end-diastolic diameter (50.4 +/- 6.3 vs. 49.3 +/- 6.1 mm), muscle mass index (189 +/- 57 vs. 197 +/- 50 g/m2), stroke volume (86.1 +/- 26.2 vs. 85.7 +/- 26.7 7 ml/m2) and fractional shortening (29.1 +/- 7 vs. 30.8 +/- 8.6%). We conclude that the predominant finding in ESRD is an LV hypertrophy progressing towards an asymmetric septum hypertrophy, while the increase of the primarily enlarged left atrial diameter over 30 months reflects a further deterioration of the diastolic LV dysfunction.

Dialysis-Induced Cardiac Arrhythmias: Fact or Fiction?

Frequency and grade of premature ventricular depolarizations were assessed in 10 patients on maintenance renal replacement therapy. All medication was withdrawn prior to the study. Each patient was treated sequentially by 8 different methods [acetate and bicarbonate hemodialysis (HD), hemofiltration, hemodiafiltration, ultrafiltration, use of 5 different membranes]. Despite marked changes in serum electrolyte concentrations there was no difference in frequency or grade of premature ventricular beats between the periods before, during, and after renal replacement therapy. Comparison of the 8 methods tested revealed no superiority of 1 method during the observation period of 192 h for each patient. In a second group of 8 patients with confirmed coronary artery disease, acetate HD had no effect on grade and frequency of ventricular arrhythmias, although arrhythmias occurred more often (p less than 0.05) and were more dangerous. We therefore conclude that the incidence of ventricular arrhythmias is primarily dependant on the presence of preexisting coronary artery disease and that HD or related methods do not increase the risk of ventricular ectopies in patients without digitalis medication.

Cardiac structure and function in continuous ambulatory peritoneal dialysis: Influence of blood purification and hypercirculation

Continuous ambulatory peritoneal dialysis (CAPD) is associated with obvious hemodynamic and blood purification advantages over intermittent hemodialysis. To determine whether this is reflected in favorable left ventricular (LV) structure and function, a group of 55 normotensive patients (aged 58.4 +/- 11.0 years) undergoing CAPD was analyzed by means of echocardiography. Characteristic findings were LV hypertrophy (158 +/- 50 gm/m2), mainly the result of septal thickening (13.3 +/- 2.8 mm), and left atrial dilatation (40.9 +/- 7.4 mm). Mean LV diameter in end diastole and end systole and posterior wall thickness were normal. Parameters of LV systolic function (ejection fraction [EF]: 62.0 +/- 13.0%; velocity of circumferential fiber shortening [Vcf]: 1.58 +/- 0.46 circ/sec) were in the upper normal range at a hyperdynamic circulatory state (cardiac index [CI] 4.67 +/- 1.82 L/min/m2. The amount of LV hypertrophy was related to the amount of hypercirculation (CI: p less than 0.001; hemoglobin: p less than 0.025) and quality of blood purification (creatinine, urea: p less than 0.02) but not to blood pressure, age, or duration of dialysis. Left atrial dilatation was inversely related to LV systolic function (EF, Vcf: p less than 0.001) and directly related to LV muscle mass (p less than 0.02). A low prevalence (13%) of pericardial effusion was independent of blood purification. We conclude that in normotensive patients receiving CAPD, a high prevalence of left atrial dilatation and asymmetric septal hypertrophy is found, the latter being related both to the amount of hypercirculation and the quality of blood purification.

Mechanisms of altered myocardial contractility during hemodialysis: Importance of changes in the ionized calcium to plasma potassium ratio

SummaryHemodialysis is associated with alterations in myocardial contractility, but duration and precise determinants responsible for these changes are unknown. We investigated the effect of several variables, established to influence left ventricular (LV) contractility, which normally changed during dialysis: the plasma concentrations of ionizied calcium, potassium, bicarbonate, and magnesium and the removal of uremic toxins. The influence of three different isovolemic bicarbonatedialysis procedures in 16 patients with normal (group 1) and hypertrophied myocardium (group 2) was assessed by echocardiography prior to and up to 44 h following each dialysis. During the first procedure, ionized calcium and potassium concentration decreased, but LV performance remained unchanged in both groups. The second procedure with increased ionized calcium and decreased potassium concentration resulted in an improvement of mean circumferential fiber shortening (VCF from 1.15 to 1.56 circ/s (P<0.001) in group 1 and from 1.05 to 1.16 circ/s (P<0.05) in group 2. The positive inotropic effect declined gradually up to 12 h (group 1) and 2.5 h (group 2) respectively. In the third procedure when ionized calcium was increased and potassium concentration remained unchanged contractility did not improve. Removal of uremic toxins, decrease in magnesium, and increase in bicarbonate concentrations were comparable during each procedure. These results suggest that the ionized calcium to potassium ratio is the important determinant of dialysis-related augmentation in LV contractility. In LV hypertrophy the expected contractile response is diminished indicating a depressed inotropic state.

Cardiovascular factors influencing survival in end-stage renal disease treated by continuous ambulatory peritoneal dialysis

To determine whether hemodynamic advantages of continuous ambulatory peritoneal dialysis (CAPD) over intermittent hemodialysis are associated with improved survival and identify cardiac risk factors for early death, 55 patients on CAPD (age 58 +/- 11 years; CAPD duration: 29 +/- 25 months) were followed in a noninvasive prospective analysis over 35 months. At follow-up, 25 patients had died; 16 deaths were related to cardiovascular causes. Nonsurvivors were older (62 +/- 8 vs 55 +/- 12 years; p less than 0.015) and had more angina pectoris (40 vs 20%; p less than 0.05) than survivors, but had comparable CAPD duration, arterial blood pressure, hemoglobin, serum creatinine, urea and parathyroid hormone concentrations. On echocardiography, nonsurvivors had a lower mean left ventricular (LV) ejection fraction (59 +/- 15 vs 66 +/- 9%; p less than 0.03), higher LV end-systolic volume indexes (49 +/- 31 vs 36 +/- 13 ml/m2; p less than 0.03) and a shorter mean LV ejection time (371 +/- 41 vs 390 +/- 22 ms; p less than 0.03). LV muscle mass, LV diastolic and left atrial dimensions, stroke volume and cardiac index were comparable. On pulsed Doppler analysis of a subgroup of 48 patients in sinus rhythm and without valve disease, nonsurvivors (n = 23) had more severely decreased ratios of peak early/atrial filling velocities (0.66 +/- 0.18 vs 0.81 +/- 0.24; p less than 0.03) and increased atrial filling fractions (52 +/- 11 vs 46 +/- 9%; p less than 0.03) than survivors. Mean isovolumic relaxation periods were increased in both groups (135 +/- 39 vs 129 +/- 33 ms; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Beeinflussung mikrosomaler Enzyme der Rattenleber durch Spironolacton, Etacrynsäure und Furosemid

SummaryMale rats weighing 80–100 g received a daily dose of 3×7 mg Spironolactone per 100 g body weight. After 8 days, a stimulation of the specific activity of isolated hepatic microsomes for the demethylation of aminopyrine (70%) and the glucuronidation of 4-Methylumbelliferone (63%) was observed. Microsomal cytochrome P-450 content increased about 66%.After 8 days, daily treatment with 2×0.15 mg etacrynic acid per 100 g body weight increased the specific activity of microsomes for demethylation of aminopyrine (41 %) and the P-450 content (37%), while the specific activity for glucuronidation of 4-Methylumbelliferone was not significantly altered.Treatment with these substances did not modify the specific activity of glucose-6-phosphatase, the cytochrome b5 content of microsomes, the microsomal protein content per gram liver, the liver wet weight and the body weight.Furosemid (2×1 mg per 100 g body weight during 8 days) did not influence the parameters measured.Zusammenfassung8tägige i. p. Vorbehandlung 80–100 g schwerer männlicher Wistarratten mit 3×7 mg/100 g KG/d Spironolacton bewirkte einen Anstieg der Aminopyrindemethylierung um 70%, der Glucuronyltransferase (mit 4-Methylumbelliferon als Substrat) um 63% und des Cytochrom P450-gehaltes um 66%. Achttägige i. p. Vorbehandlung mit 2×0,15 mg/100 g KG/d Etacrynsäure hatte einen Anstieg der Aminopyrindemethylierung um 41% und des Cytochrom P450-gehaltes um 37% zur Folge.Absolutes und relatives Leberfeuchtgewicht (bezogen auf 100 g KG), Mikrosomenproteingehalt/g Leber, Cytochrom b5-Gehalt und spezifische Aktivität der Glucose-6-Phosphatase wurden durch keine der genannten Substanzen beeinflußt. Es handelt sich somit um eine spezifische Stimulierung pharmakaabbauender Enzyme. Achttägige Vorbehandlung mit 2×1 mg/100 g KG Furosemid/d bewirkte keine Beeinflussung der untersuchten Parameter.

Untersuchungen zum Einfluß der Urämie auf die Metabolisierung von Phenylbutazon und Aminophenazon beim Menschen

Summary20 uremic patients with normal liver function received a single oral load of either 6 mg Phenylbutazone/kg or 12 mg Aminophenazone/kg body weight. Subsequently, the decay of plasma concentrations and plasma half-lifes of both drugs were estimated. The results were compared with the values obtained in control groups showing normal kidney and liver functions.24 hr after treatment with Phenylbutazone, uremic patients had an average plasma concentration of 1.75±0.91 mg Phenylbutazone/100 ml, compared to 4.3±0.85 mg/100 ml in controls. In the latter, the plasma half-life of Phenylbutazone corresponded to 50.9±13.5 hr, while in uremic patients plasma half-life was approximately 48% higher (75.4±12.8 hr).4 hr after the administration of Aminophenazone, the same plasma concentrations (1.03±0.45 mg/100 ml and 0.99±0.31 mg/100 ml, respectively) were observed in uremic patients and the control group. In uremic patients, Aminophenazone plasma half-life was 4.1±1.6 hr compared to 4.0±1.7 hr in control subjects. Plasma half-lifes of Aminophenazone and Phenylbutazone were not correlated to the urea and creatinine serum concentrations measured.Both drugs are eliminated by degradation in the liver endoplasmic reticulum through the mixed function oxydation pathway. It is therefore concluded that in man, uremia causes a slow-down of the oxidative metabolism of some lipophilic drugs, but not of all, as found in uraemic rats.ZusammenfassungJe 10 urämische Patienten und nierengesunde Probanden mit normaler Leberfunktion erhielten entweder 6 mg Phenylbutazon/kg oder 12 mg Aminophenazon/kg KG per os. Beide Pharmaka werden durch mischfunktionelle Oxygenierung im endoplasmatischen Reticulum der Leber abgebaut.Anschließend wurden zu bestimmten Zeiten die Plasmakonzentrationen gemessen und die Plasmahalbwertszeiten beider Substanzen ermittelt.24 h nach Phenylbutazongabe wurde bei Nierengesunden eine mittlere Plasmakonzentration von 4,3±0,85 mg/100 ml gemessen, bei Urämikern dagegen nur 1,75±0,91 mg/100 ml.Die mittlere Plasmahalbwertszeit betrug bei Nierengesunden für Phenylbutazon 50.9±13.5 h, bei Urämikern war sie um 48% auf 75.4±12.8 h verlängert.4 h nach oraler Gabe von Aminophenazon betrug die Plasmakonzentration von Aminophenazon bei Nierengesunden 0,99±0,31 mg/100 ml, bei Urämikern 1,03±0,45 mg/100 ml. Bei urämischen Patienten wurde eine mittlere Aminophenazonhalbwertszeit von 4.1 ± 1.6 h, bei Urämikern von 4.0±1.7 h gemessen.Es bestand keine signifikante Korrelation zwischen den Serumkonzentrationen von Harnstoff oder Kreatinin einerseits und der Plasmahalbwertszeit von Phenylbutazon oder Aminophenazon andererseits.Aus diesen Ergebnissen und den in der Literatur mitgeteilten Befunden wird geschlossen, daß beim Menschen unter den Bedingungen der Urämie eine Beeinflussung des oxydativen Abbaus einzelner lipophiler Pharmaka eintritt. Allgemein gütige Regeln bezüglich der Dosierung von Arzneimitteln, die durch mischfunktionelle Oxygenierung metabolisiert werden, können bei urämischen Patienten aber bis jetzt nicht gegeben werden, da offensichtlich der Abbau verschiedener Substanzen durch die Urämie unterschiedlich beeinflußt wird.

Adenylate Cyclase and Alpha-2-Adrenoceptors in Thrombocytes of Chronic Uremic Patients

Thrombocyte adenylate cyclase regulation and alpha-2-adrenoceptors have been studied in uremic patients as well as in healthy controls. Stimulation of adenylate cyclase activity by PGE1 and forskolin as well as inhibition by (+/-)-epinephrine was not significantly different between both groups. Additionally, there was no evidence of an alteration of the thrombocyte alpha-2-adrenoceptor density, determined by 3H-rauwolscine binding as suggested by others.

Impaired intestinal digoxin absorption in experimental chronic uremia.

Using a modified everted sac preparation, intestinal absorption of 3H-digoxin was studied in rats. Chronic renal failure decreased mucosa to serosa transport and net transport significantly

Effect of uremia on drug-degrading enzymes in rat liver microsomes

SummaryMale Wistar rats weighing about 250 g underwent subtotal nephrectomy. 6 days after urea concentration in serum was 331.4±100.2 mg %, and creatinine concentration 4.0±0.75 mg % respectively. Body weight decreased from 251±10.7 g to 197±15.3 g, liver weight decreased about 23% compared to controls. Liver weight per 100 g body weight was the same in both nephrectomized rats and controls. Livers were removed and microsomes isolated by differential centrifugation on the 6th day after operation. Specific activity of the demethylation of aminopyrine decreased from 7.96±0.60 (controls) to 5.15±0.65 in uremic rats, microsomal Cytochrome P-450 content from 0.066±0.005 to 0.046±0.005 (E450–490×mg Prot−1×cm−1). No differences were observed in specific activity of glucose-6-phosphatase and microsomal Cytochrome b5 content between controls and uremic animals.Zusammenfassung6 Tage nach subtotaler Nephrektomie entwickelte sich bei 250 g schweren männlichen Wistarratten eine Urämie mit einer Harnstoffkonzentration i. S. von 331.4±100,2 mg-% und einer Kreatininkonzentration von 4,0±0,75 mg-%. Gegenüber scheinnephrektomierten Kontrolltieren erlitten die Versuchstiere eine Abnahme des Körpergewichtes um ca. 21 % und des Leberfeuchtgewichtes um ca. 23 %, während bezüglich des auf 100 g Körpergewicht bezogenen relativen Lebergewichtes keine Unterschiede auftraten. Die spezifische Aktivität der Aminopyrindemethylierung der isolierten Lebermikrosomen betrug bei urämischen Tieren 5,15±0,65 (nM×mg Prot−1×min−1), der mikrosomale Cytochrom-P-450-Gehalt 0,046±0,005 (Δ E450–490×mg Prot−1×cm−1), bei Kontrolltieren 7,96±0,60 bzw. 0,066±0,005, beide Unterschiede sind signifikant. Bezüglich der spezifischen Aktivität der Glucose-6-Phosphatase und des Cytochrom-b5-Gehaltes waren zwischen beiden Kollektiven keine Unterschiede nachweisbar.Male Wistar rats weighing about 250 g underwent subtotal nephrectomy. 6 days after urea concentration in serum was 331.4±100.2 mg %, and creatinine concentration 4.0±0.75 mg % respectively. Body weight decreased from 251±10.7 g to 197±15.3 g, liver weight decreased about 23% compared to controls. Liver weight per 100 g body weight was the same in both nephrectomized rats and controls. Livers were removed and microsomes isolated by differential centrifugation on the 6th day after operation. Specific activity of the demethylation of aminopyrine decreased from 7.96±0.60 (controls) to 5.15±0.65 in uremic rats, microsomal Cytochrome P-450 content from 0.066±0.005 to 0.046±0.005 (E450–490×mg Prot−1×cm−1). No differences were observed in specific activity of glucose-6-phosphatase and microsomal Cytochrome b5 content between controls and uremic animals.