Peter Kulzer

Role of Bradykinin in Anaphylactoid Reactions during Hemodialysis with AN69 Dialyzers

In vitro experiments have related anaphylactoid reactions in patients treated with angiotensin-converting enzyme (ACE) inhibitors during dialysis with AN69 membranes to excessive bradykinin generation using this negatively charged dialysis membrane. In the present clinical trial plasma bradykinin levels were followed during the early phase of dialysis in 10 patients, not being treated with ACE inhibitors, using AN69, cuprophane, and polysulfone membranes. Bradykinin was measured after extraction by radioimmunoassay. During this study one episode of anaphylaxis occurred during dialysis with the AN69 membrane. Blood samples were collected during the first 5 min of the adverse reaction and showed a more than 100-fold increase in the venous effluent of the AN69 dialyzer (baseline 40 +/- 3 vs. 4,900 +/- 130 fmol/ml after 5 min). Even though none of the patients received ACE inhibitors, there were 4 more asymptomatic individuals who displayed a more than two-fold increase in their plasma bradykinin concentrations in the venous effluent of the AN69 dialyzer. When these patients were treated either with cuprophane or with polysulfone dialyzers, no significant bradykinin formation was detected, nor were there any adverse events. Taken together, these findings show that anaphylactoid reactions with the AN69 membrane are due to excessive bradykinin generation which even may occur in the absence of ACE inhibitors.

Evidence for reduced catabolism by the antiglucocorticoid RU 38486 in acutely uremic rats

Previous studies suggested that increased blood levels of, or increased tissue sensitivity to, glucocorticoids may contribute to catabolism in acute uremia. To examine this possibility we determined urea nitrogen (urea-N) appearance, plasma levels of Nt-methylhistidine and the activity of the alkaline myofibrillar proteinase in acutely uremic rats with and without treatment with RU 38486, a selective antiglucocorticoid. Forty-eight hours after bilateral nephrectomy, the rats had markedly elevated serum levels of urea-N, creatinine, potassium and phosphorus. In uremic rats receiving RU 38486, comparable levels of serum creatinine were found, but the serum levels of urea-N (221 +/- 4 vs. 259 +/- 5 mg/dl) and phosphorus (6.5 +/- 0.3 vs. 8.5 +/- 0.4 mmol/l) were significantly decreased as compared to uremic animals without RU 38486. In comparison to sham-operated rats, urea-N appearance (net urea production) was increased by 56% 48 h after bilateral nephrectomy. This increment was almost completely reversed in uremic animals receiving the antiglucocorticoid. In untreated uremic rats, plasma levels of Nt-methylhistidine were 10.3 +/- 0.9 microgram/dl, whereas the administration of RU 38486 caused a significant decline in the levels of this amino acid (7.6 +/- 0.5 microgram/dl). This reduction in Nt-methylhistidine was associated with a concomitant decrease of myofibrillar proteinase activity in muscle tissue homogenates. Compared to sham-operated animals, this proteinase activity was increased by 30% in uremic rats, but was normal in those given RU 38486. Taken together, these data support the view that in acute uremia accelerated ureagenesis occurs, while enhanced muscle protein breakdown, owing to an increment in myofibrillar proteinase activity, provides the necessary amino acid precursors.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness and safety of recombinant human erythropoietin (r-HuEPO) in the treatment of anemia of chronic renal failure in non dialysis patients. European Multicentre Study Group.

Seventy-five non-dialized patients with chronic renal failure (CRF) and severe renal anemia were enrolled in a study, receiving r-HuEPO subcutaneously thrice weekly for 6 months. In 64 patients (85%) 7 weeks of treatment with a weekly dose of 158 U/kg were required to achieve Hb concentrations within the target range of 10 to 12 g/dl. Of the 11 patients (15%) who failed to achieve the target Hb range, none were considered to be non-responders as they were excluded for unrelated reasons prior to week 16 (8 cases), or were iron deficient (2 cases), or had bleeding complications (1 patient). Maintaining the Hb concentration at a level of 10.5 g/dl required a mean r-HuEPO dose of 92 U/kg per week. Adverse events were generally mild or moderate. The most commonly reported were hypertension (8%), viral infection/including flu-like syndrome (7%), nausea (7%), and dizziness (5%). Statistically significant increases in mean creatinine concentrations observed after 12 and 24 weeks were most likely due to the progression of renal disease. These results confirm that 50 U/kg of r-HuEPO given 3 times per week subcutaneously provide a safe and effective therapy for anemic predialysis patients.

Chronic ethanol ingestion enhances catabolism and muscle protease activity in acutely uremic rats.

Skeletal muscle wasting in men as well as enhanced urea production in animals due to ethanol consumption has been demonstrated by numerous authors. Furthermore, the outcome of acute renal failure is closely related to the extent of catabolism. The present study was performed to investigate whether chronic ethanol exposition prior to binephrectomy (BN) may represent a predisposing factor for enhanced protein breakdown. Rats underwent BN after exposure to ethanol or isocaloric substrate for 4 weeks. Blood chemistries and muscle samples were obtained 48 h after BN. Animals fed with ethanol revealed significantly higher levels of serum urea nitrogen (SUN) and urea nitrogen appearance (UNA) in comparison to controls. Preconditioning on ethanol-derived calories induced an accelerated fractional degradation rate of myofibrillar protein as demonstrated by a significantly enhanced serum Nt-methylhistidine/creatinine ratio. The increase in serum indicators of enhanced myofibrillar breakdown correlated with the stimulated activities of alkaline myofibrillar protease and cathepsin B. Finally, serum corticosterone levels were enhanced in the experimental group in comparison to controls, indicating an ethanol-related adrenocortical stimulation to be a possible mediating factor of enhanced catabolism in ARF. Thus, chronic ethanol intake prior to the onset of ARF seems to be a risk factor for enhanced catabolism in the course of acute uremia.

HORMONAL REGULATION OF MUSCLE PROTEIN CATABOLISM IN ACUTELY UREMIC RATS: EFFECT OF ADRENALECTOMY AND PARATHYROIDECTOMY

To examine the role of glucocorticoids and PTH on the enhanced protein catabolism of acute uremia, rats were rendered uremic and had their adrenals or their parathyroid glands concomitantly removed. Adrenalectomy resulted in a marked reduction of urea generation in uremic animals due to decrease of myofibrillar protein breakdown as indicated by lower serum levels of Nt-methylhistidine and a reduction in the activity of the myofibrillar proteinase from skeletal muscle. This reduced urea formation was accompanied by marked hypoglycemia. Parathyroidectomy, on the other hand, caused no change of those parameters of protein catabolism, suggesting that PTH does not account for the protein degradation observed in acutely uremic rats.

Eglin C fails to reduce catabolism in acutely uremic rats.

Increased release of proteinases from polymorphonuclear leukocytes, namely elastase, has been incriminated to take part in the pathogenesis of enhanced muscle protein breakdown in acute renal failure. In order to investigate, whether inhibition of the granulocyte proteinase elastase and cathepsin G would have a beneficial effect on the extent of muscle protein degradation, eglin C, a potent inhibitor of the granulocyte proteinase elastase and cathepsin G, was administered intraperitoneally to acutely uremic rats. 48 hours after bilateral nephrectomy, eglin C-treated animals displayed no significant difference, as far as serum levels of SUN, glucose and Nt-methylhistidine are concerned. Similarly, eglin C treatment failed to reduce the stimulated activity of the alkaline myofibrillar proteinase in comparison to binephrectomized controls. Hence, according to these results, granulocyte proteinases do not seem to be an important mediator of uremic catabolism, since their inhibition by eglin C does not reduce enhanced protein breakdown in acutely uremic rats.

Evidence for the Role of Proteinases in Uremic Catabolism

Enhanced muscle protein breakdown has been demonstrated in acutely uremic rats by numerous authors. In order to investigate the pathogenetic role of skeletal muscle proteinases leupeptin, a low-molecular weight proteinase inhibitor, was administered intraperitoneally to acutely uremic rats. Twenty-four hours after bilateral nephrectomy, leupeptin-treated animals displayed significantly lowered serum urea levels (-32%), as compared to untreated uremic rats. As a sign of muscle protein breakdown, plasma levels of Nt-methylhistidine, an indicator of myofibrillar protein degradation, were also decreased (-35%) in the uremic animals treated with leupeptin as compared to untreated uremic rats. Finally, leupeptin treatment resulted in a significant inhibition of the myofibrillar alkaline proteinase activity, a proteinase which has been related to various catabolic conditions. These findings suggest that the increased muscle protein breakdown in uremia is caused by enhanced activity of muscular proteinases and that anti-proteolytic agents display favourable effects on the enhanced protein degradation observed in acute uremia.