Abetraet. The effect of acute uraemia on glucose and urea formation by isolated perfused liven of fasting rats was investigated.The basal gluconeogenesis following nephrectomy was significantly increased as compared to normal and sham operated controls. Enhanced glucose formation was associated with an increase in both urea synthesis and output of the p r l y metabolizable amino acids valine, leucine, and isoleucine. In the presence of a mixture of amino acids (serine, threonine, lysine, glutamic acid, ornithine, and citrnlline) all added at near physiological concentrations, the stimulating effect of uraemia on gluconeogenesis was further enhanced. This was paralleled by an increased formation of urea and an increased uptake of the amino acids. It is concluded that acute uraemia may stimulate glucose synthesis by increased substrate supply. This seems to be achieved by a t least two different mechanisms, namely increased protein degradation and accelerated amino acid utilization.

Plasma levels and diuretic response were determined in seven healthy subjects and six patients with severe nephrotic syndrome (NS) after 40 mg furosemide (Fu). Mean apparent volume of distribution and distribution volume at steady state of the groups did not differ. Total Fu clearance was higher in NS (251 +/- 54 ml/min) that in healthy subjects (174 +/- 32 ml/min) (P less than 0.01), a difference that correlated with the nonrenal clearance of 56 +/- 28 ml/min in healthy subjects and 154 +/- 45 ml/min in patients with NS (P less than 0.001). Normal beta-elimination half-life of 51 +/- 7.7 min was 37 +/- 6.2 min (P less than 0.001) in NS. Mean normal Fu protein binding pf 98.6 fell to 97.2%, with decreasing plasma albumin levels. After 40 mg IV Fu, sodium and volume excretion decreased in NS (P less than 0.001 and P less than 0.005). In patients Na+/Fu excretion rate ratios showed "tubular resistance" to Fu over the time when large amounts of Fu were excreted. The reduced diuretic response to Fu in NS is taken to be mainly a consequence of its impaired renal excretion.

After rapid intravenous injection of furosemide 40 mg (Fu), plasma levels were determined in 7 healthy volunteers, 8 patients with liver cirrhosis with ascites and 7 patients with end-stage renal disease (ESRD). The diuretic response was evaluated by measuring the urinary excretion of sodium and potassium and the urine volume. The mean elimination half life (t 1/2 beta) of Fu averaged 51 +/- 7.7 (+/- SD) min in healthy subjects, 52 +/- 7.7 min in cirrhosis and 200 +/- 57 min in ESRD. The non-renal clearance (Clnr) in healthy subjects (56 +/- 28 ml/min) corresponds to the total plasma clearance in functionally anephric patients (54 +/- 18 ml/min). In cirrhosis there was no significant change in the disposition parameters of Fu in comparison to the healthy volunteers, but there was a significant reduction in urine sodium and volume, whereas potassium excretion remained unchanged. Fu "excretion rate--response" curves showed diminished tubular sensitivity to Fu in cirrhosis.

The disposition profile of ceftriaxone was studied in 12 functionally anephric patients (creatinine clearance less than 10 ml/min) who received bolus injections of 150, 500, and 1500 mg IV in a noncrossover fashion. As in healthy subjects, the kinetics in uremic patients were nonlinear for total (bound plus unbound) and linear for free (unbound) drug. The plasma protein binding was reduced due to a decreased association constant, resulting in a doubling of the free fraction in plasma. Ten of 12 patients showed nonrenal clearance values of unbound drug (ClFNR) identical to those in healthy adults and only minor increases in their biologic t1/2(beta) compared to normal (12 and 8 hr). These patients would require no dose adjustments in their dosing regimen. Two of the patients exhibited decreased ClFNR values and increased t1/2(alpha) of 20 and 34 hr. Anephric patients with impaired nonrenal elimination would require minor dose adjustments.

Experiments were performed to elucidate the mechanisms involved in the enhanced conversion of amino acids to glucose in acute uraemic rats. Increased gluconeogenesis from a mixture of serine, threonine, lysine, glutamate, ornithine and citrulline was confirmed using a non-recirculating perfusion system. Stimulation was concentration dependent, being most pronounced at physiological amino acid concentrations. Stimulation of glucose and urea formation could be mimicked by using serine alone whereas with lactate and pyruvate inhibition of gluconeogenesis was observed. Serine dehydratase activity was significantly elevated following nephrectomy. Further, the uptake of the non-metabolize amino acid alpha-aminoisobutyrate was considerably increased. It is concluded that serine may play a special role as substrate for the additional glucose formation in acute uraemic rats, probably mediated by an activation of serine dehydratase. Acceleration of amino acid transport seems to represent an additional component of stimulation of amino acid utilization in acute uraemia.

Abetraet. The effect of acute uraemia on glucose and urea formation by isolated perfused liven of fasting rats was investigated.The basal gluconeogenesis following nephrectomy was significantly increased as compared to normal and sham operated controls. Enhanced glucose formation was associated with an increase in both urea synthesis and output of the p r l y metabolizable amino acids valine, leucine, and isoleucine. In the presence of a mixture of amino acids (serine, threonine, lysine, glutamic acid, ornithine, and citrnlline) all added at near physiological concentrations, the stimulating effect of uraemia on gluconeogenesis was further enhanced. This was paralleled by an increased formation of urea and an increased uptake of the amino acids. It is concluded that acute uraemia may stimulate glucose synthesis by increased substrate supply. This seems to be achieved by a t least two different mechanisms, namely increased protein degradation and accelerated amino acid utilization.

Urea‐cycle enzymes and omithine‐ketoacid‐transaminase have been measured in biopsy specimens of liver from healthy subjects and from patients suffering from alcoholic hepatitis. Both groups of subjects received a hospital diet of about 100 g of protein daily. Extraction of enzymes from biopsy specimens was performed by a standardized technique.–The DNA content of liver did not vary significantly between the groups, whereas protein content was significantly lower in patients with alcoholic hepatitis than in controls (p < 0.05). Of the enzymes tested, the activities of carbamyl‐phosphate synthetase and arginase were significantly decreased (p < 0.05 and p < 0.005 respectively) in patients with alcoholic hepatitis. Activities of arginosnccinate lyase, ornithine‐ ketoacid‐transaminase and ornithine‐carbamylphosphate transaminase remained unchanged in both groups.–These results demonstrate that alterations in arginase and carbamylphoa‐phate synthetase‐activities in the liver of patients with alcoholic hepatitis precede the histological manifestation of liver cirrhosis, which is associated with a significant decrease in some urea cycle enzymes [3, 15, 16]. Therefore the determination of arginase and carbamylphosphate synthetase in needle‐biopsies of human liver represent sensitive parameters of liver cell necrosis during the course of alcoholic hepatitis.

Abstract. Enzyme activities of the glycolytic, gluconeogenic, and hexose monophosphate pathways were measured in the liver of starved rats 12 and 48 hours after bilateral nephrectomy. Control experiments (sham operated rats) revealed that alterations of enzyme activities were not due to uraemia but to starvation. Alanine‐aminotransferase and aspartate‐ aminotransferase activities, however, were significantly elevated in rat liver 48 hours after nephrectomy when compared with sham operated controls. Concentrations of some of the gluconeogenic intermediates (3‐phosphoglyceric acid, pyruvate, phosphoenolpyruvate and glucose‐6‐phosphate) were significantly higher in the liver of uraemic animals. Amino acid analysis showed an increase in only L‐alanine concentration. It is suggested that the elevated content of pyruvate in the liver during acute uraemia is due to an inhibition of pyruvate degradation. Together with the elevated pyruvate concentration the increase in L‐alanine could be explained as a consequence of the equilibrium of the alanine‐aminotransferase reaction; Kapp. of the reaction is not changed by uraemia. Increased activities of the transaminases and the elevated concentrations of the other metabolites measured might indicate that in the liver of nephrectomized rats there is enhanced gluconeogenesis from substrates other than pyruvate.