Acute Uremia Research Articles

Tissue catecholamines in obstructive nephropathy and acute uremia in the rat.

Previous studies have shown that the 24-h unilateral ureteral obstructed kidney (UUO) responds to acute renal denervation after relief of obstruction with an increase in glomerular filtration rate (GFR), renal plasma flow (RPF), natriuresis, and diuresis, while the 24-h bilateral ureteral obstructed kidney (BUO), undergoing postobstructive diuresis after relief of obstruction, shows no response to acute denervation. In the present study, renal tissue norepinephrine (NE) content and concentration were found to be markedly decreased in the BUO kidney suggesting partial renal denervation, while renal NE content was normal in the UUO kidney. The decrease in renal NE content in the BUO kidney was organ specific since myocardial NE was not affected, and was not due to acute uremia, since rats made uremic by 24 h of total intravenous urine reinfusion showed no change in renal NE content. Renal dopamine content was markedly increased in the UUO kidney, perhaps as a result of renal decarboxylation of dopa and failure of excretion, while renal and myocardial epinephrine content were increased in the BUO and urine reinfused groups, both of which were subjected to the stress of acute uremia. The decrease in renal NE content in the kidney undergoing postobstructive diuresis after relief of 24-h BUO probably indicates damage to sympathetic nerve terminals by high intrarenal pressure during BUO and suggests that partial renal denervation could contribute to the functional changes observed in this experimental model.

Glycogen Synthesis from Serine in Isolated Perfused Hindquarters of Acutely Uraemic Rats

Isolated hindquarters of bilaterally nephrectomized and sham-operated rats were perfused in the presence and absence of 14C-labelled serine, respectively. After a perfusion period of 30 min 14C-serine was 4,074 +/- 270 dpm/ml in the perfusion medium of sham-operated animals and decreased to 2,800 +/- 190 dpm/ml in the medium of acutely uraemic rats. Muscle glycogen concentration in sham-operated animals was 1.10 +/- 0.04 mg/g wet weight in the absence and 1.03 +/- 0.11 mg/g in the presence of serine. In contrast, in acutely uraemic rats there was a glycogen concentration of 0.57 +/- 0.09 mg/g in the absence of serine. Glycogen was increased in the presence of serine in the perfusion medium, the value being 1.50 +/- 0.13 mg glycogen/g wet weight. Incorporation of labelled serine into skeletal muscle glycogen was significantly higher in acutely uraemic animals (15 +/- 0.5 mumol/g glycogen) than in sham-operated animals (10 +/- 0.4 mumol/g). The results are compatible with the hypothesis that serine increases muscle glycogen synthesis in acute uraemia.

Extraction of parathyroid hormone and release of adenosine 3',5'-monophosphate by isolated perfused bones obtained from dogs with acute uremia.

To study the direct effect of PTH on bone in acute uremia, we examined the effects of bilateral nephrectomy (BNX) and a combination of BNX and thyroparathyroidectectomy (TPTX) on the arteriovenous difference of PTH-(1–34) and the release of cAMP by the isolated perfused tibia of the dog. Normal dogs were subjected to BNX or TPTX-BNX, and 42 h later, the tibiae were removed for perfusion. The immunoreactive PTH levels in plasma were significantly elevated in the BNX group. The mean extraction of PTH-(1–34) by bone was 46.7 ± 6.3% in the control group and not significantly different in any of the experimental groups. The release of cAMP increased significantly in all groups (P < 0.005 to P < 0.001) after the administration of PTH-(1–34). The cumulative release of cAMP per 30 min was significantly diminished (P < 0.001), compared to controls, in the BNX groups, but was normal in the TPTX-BNX group. In conclusion, isolated perfused bones from acutely bilaterally nephrectomy dogs release less cAMP in response ...

Peripheral nerve function in acute and chronic uremia in rats.

There is good evidence that uremic neuropathy is due to a dialysable toxin which causes a generalised and reversible slowing of the nerve conduction velocity (for review see Nielsen 1979). However, the toxin has not been identified and its mode of action is unknown. The present report describes the peripheral nerve function in acute and chronic experimental uremia.

Isolation of protein-glycogen complexes from rat skeletal muscle in acute uremia: role of serine.

AbstractAttempts were made to isolate an intact protein–glycogen complex from rat skeletal muscle in acute and chronic uremia and after different treatment regimes. In control animals the amount of glycogen in the 30-pellet fraction was 16.5 mg and in rats with chronic uremia 27.6 mg. The yields of glycogen phosphorylase and synthetase do not correlate with the quantity of glycogen during isolation. In the presence of ATP, calcium, and magnesium, flash activation of phosphorylase was four to six times slower in rat than in rabbit muscle. In acute uremia, after feeding a mixed low-protein diet and Walser ketoacid mixture, a protein–glycogen complex could not be isolated. Additional administration of propranolol resulted in yields of only 10 and 7 μg glycogen after binephrectomy and ureter ligation, respectively. In contrast, glycogen concentration increased dramatically after sham operation (4.55 mg glycogen/mg protein). Additional administration of high doses of serine resulted in an increase of glycogen ...

Lymphocyte kinetics in acute uremia: redistribution of circulating lymphocytes to the bone marrow.

The mechanism(s) responsible for the peripheral blood lymphocytopenia found in uremia was investigated. Inbred Magnum guinea pigs were made uremic by ureteral ligation, and 1 day later injected with chromium (Cr)51-labeled syngeneic lymphocytes intravenously. 1 day later, the animals were sacrificed and organs counted for radioactivity. Sham-operated animals served as controls. Radioactivity in the lung and liver was the same or greater in the sham-operated animals than in uremic animals. In the blood and spleen, radioactivity was slightly higher in the uremic animals, while in the long bones this was significantly higher. In uremia therefore, there appears to be a redistribution of circulating lymphocytes to the bone marrow. The resultant lymphocytopenia may play a role in the immunologic incompetence seen in uremia.

Reflections on the role of carbon haemoadsorption in therapeutic medicine.

The selection of Norit RBX-1-activated carbon granules for blood detoxification by haemoadsorption is outlined. Synthetic polymer membranes have been coated on to this carbon by a specially developed process and perfusion devices prepared from these materials have been evaluated in animal models of acute poisoning and liver failure. Clinical application of carbon haemoadsorption has been explored in acute poisoning, liver failure and uraemia. The experience to date would suggest that carbon will have to be augmented by other adsorbent species before life support systems based principally on haemoadsorption become a reality especially in the treatment of uraemia and in liver failure. A secondary role as a temporary adjunct to dialysis has been established for carbon haemoperfusion in the treatment of uraemic pericarditis and is under further investigation in the treatment of pruritus, pigmentation and neuropathy.

Effect of hormones on hepatocyte gluconeogenesis in different models of acute uraemia.

Hepatocytes isolated from the livers of starved, sham-operated, bilaterally nephrectomised and ureter-ligated rats as well as rats with ischaemic acute renal failure were used for a comparative study of the effects of different hormones on gluconeogenesis. In all tested groups dibutyryl-3':5'-adenosine monophosphate inhibits glucose synthesis from pyruvate whereas this process is not affected by glucagon and only slightly activated by adrenalin. In contrast, gluconeogenesis from dihydroxyacetone was stimulated by all three hormones at the expense of the conversion of dihydroxyacetone to lactate. In the presence of l-serine adrenalin, glucagon and dibutyryl cAMP also stimulate glucose synthesis, which is more marked in bilaterally nephrectomised and ureter-ligated animals. In half of the experiments with bilaterally nephrectomised rats (group BN 2), lack of sensitivity of hepatocytes to all tested hormones on gluconeogenesis from serine or dihydroxyacetone was observed. The beta-adrenergic antagonist propranolol reduced the stimulatory effect of adrenalin on glucose synthesis from serine and abolished the influence of catecholamines in the presence of dihydroxyacetone and pyruvate. This suggests that both alpha- and beta-receptors are involved in the activation of hepatic gluconeogenesis. Insulin and parathyroid hormone did not change the rate of glucose synthesis in any of the experimental groups.

The gluconeogenetic ability of hepatocytes in various types of acute uraemia.

Liver cells were prepared from untreated controls, rats with various models of acute uraemia (uranyl nitrate-treated, bilaterally nephrectomised and ureter-ligated rats, rats with acute ischaemic renal failure) and sham-operated animals. Hepatocyte glucose output, pyruvate utilisation and lactate production were determined in the presence of Krebs-Ringer bicarbonate buffer with different pH values (7.1, 7.4, 7.6) using pyruvate, dihydroxyacetone, serine and fructose as substrates. In the presence of pyruvate and dihydroxyacetone a significant increase of glucose production in hepatocytes from bilaterally nephrectomised and ureter-ligated rats was observed. However, pyruvate-generated glucose production in the hepatocytes of uranyl nitrate-treated animals was unchanged, while a diminished glucose output was seen in the presence of dihydroxyacetone. A marked increase in glucose and lactate production in the presence of serine was observed in the hepatocytes of uranyl nitrate-treated, ureter-ligated and binephrectomised rats. However, lactate production from dihydroxyacetone in the liver cells of uranyl nitrate-treated animals was inhibited. In contrast to other types of uraemia, in acute ischaemic renal failure there is significantly lower hepatocyte glucose production using pyruvate as a substrate, but unchanged glucose generation from dihydroxyacetone or serine.

Influence of triiodothyronine, amphetamine, and dinitrophenol (DNP) on the reduced metabolic rate in uremic and acidotic rats

In acute HCl-induced acidosis and in acute uremia due to bilateral nephrectomy oxygen consumption is reduced by about 50%. This is normalized by amphetamine treatment in the uremic state or prevented by triiodothyronine pretreatment in acidosis. The lipolytic effects of both, triiodothyronine and amphetamine, are present under acidosis as well as under uremia. The investigations suggest that different mechanisms are responsible for the reduction of the metabolic rate in acidosis and uremia; on principle, normalization of the metabolic defect is possible.

Amino acid release from the hindquarter and urea appearance in acute uremia.

Hepatic urea production is increased in acutely uremic rats, but it is not known whether this is related to release of nitrogen from nonhepatic tissues. Rats with acute uremia had lower arterial concentrations of alanine, glutamine, and alpha-amino nitrogen when compared to sham-operated rats and released significantly more alpha-amino nitrogen from the hindquarter in situ. Release of alpha-amino nitrogen, alanine, and glutamine from the perfused hindquarter of acutely uremic rats was greater than that of sham-operated rats. These changes in situ and in the perfused hindquarter were more pronounced in rats deprived of food and water compared to fed animals and were not due to depletion of intracellular amino acids. In addition to increased amino acid nitrogen release, there was a higher urea appearance rate (excretion plus accumulation) in starved, uremic rats compared to sham-operated controls (244.7 +/- 11.2 vs. 182.0 +/- 12.4 mg. 100 g-1 .48 h-1); urea appearance also was suppressed partially by feeding. Both peripheral release of amino acids and diet influence waste nitrogen production in acute uremia.

Metabolic studies of adipose tissue in acute uremia

The effect of acute uremia on lipoprotein lipase (LPL) activity in rat adipose tissue and on the response of the isolated adipocytes to insulin was assessed. LPL activity in adipose tissue and in adipocytes of the uremic rats was decreased compared with values in sham-operated controls. Also, the adipocytes from uremic rats released significantly less than control amounts of LPL. In contrast, glucose oxidation by adipocytes isolated from uremic rats was not different from controls, and there was no difference in insulin binding or in insulin-stimulated glucose oxidation in the two groups. Triglyceride injected into the uremic rats was cleared at about half the control rate. Thus, the specific reduction in LPL activity in adipose tissue may be responsible, at least in part, for the defective removal of triglyceride. However, it is unlikely that the reduced LPL is due to a generalized toxic effect of uremia on adipose tissue since no significant alteration in insulin binding and glucose oxidation was found.

Effects of thyroparathyroidectomy, phosphate depletion and diphosphonate therapy on acute uraemic extra-osseous calcification in the rat.

1. The effects of acute uraemia on arterial and visceral calcium concentrations were studied in acutely uraemic rats. The influences of thyroparathyroidectomy, phosphate depletion and diphosphonate therapy on extra-osseous calcium concentrations were assessed in this model. 2. Aortic and visceral calcium concentrations were greater in acutely uraemic rats than in non-uraemic rats. Both prior thyroparathyroidectomy and prior phosphate-depletion resulted in lower aortic and visceral calcium concentrations in non-uraemic rats and prevented the increase in aortic and visceral calcium concentrations with acute uraemia. Diphosphonate given for 5 days before and for 2 days after the induction of acute uraemia resulted in lower tissue calcium concentrations than in non-diphosphonate-treated acutely uraemic rats. In contrast, diphosphonate given only immediately before or only after induction of acute uraemia did not prevent the increase in extra-osseous calcium concentrations with acute uraemia. 3. It is concluded that acute uraemia results in an increase in arterial and visceral calcium concentrations. Both thyroparathyroidectomy and phosphate depletion are effective in preventing the increase in extra-osseous calcium concentrations in acute uraemia. Diphosphonates may have a future role in preventing such calcification.

Prolactin metabolism in the rat: role of the kidney in degradation of the hormone.

The contribution of impaired prolactin (PRL) degradation to the altered dynamics of this hormone in uremia was investigated in rats. Hyperprolactinemia developed after bilateral nephrectomy (BNx) or ligation of both ureters (BUL), whereas PRL levels remained normal in comparably azotemic animals undergoing urine autoinfusion in which glomerular filtration rate (GFR) was maintained. The renal organ clearance of PRL in control rats accounted for two-thirds of its metabolic clearance rate and was consistently less than GFR. Following BUL and BNx the metabolic clearance of PRL decreased predictably also by two-thirds. The importance of the renal parenchyma in the degradation of prolactin was confirmed during perfusion of isolated rat kidneys. Renal PRL handling involves mainly glomerular filtration and tubular reabsorption, although uptake from peritubular blood is also demonstrable under the high plasma flow conditions obtaining during in vitro kidney perfusion. We conclude that the hyperprolactinemia associated with acute uremia in the rat is not the consequence of the uremic state per se, but results from impaired renal degradation of the hormone.

Insulin and the in vitro protein synthesis of liver and skeletal muscle ribosomes in experimental acute uraemia.

Tissue dependent alteration of liver and muscle protein synthesis was previously observed in acute uraemia, when intracellular amino acids were used as substrate. Since protein synthesis depends also on substrate availability, it was of interest to investigate the role of isolated liver and skeletal muscle ribosomes of nephrectomized rats and their susceptibility to in vivo insulin stimulation. Under marked uraemic conditions, no difference was demonstrated between controls and uraemic animals; after insulin administration and in the presence of endogenous messenger both liver and muscle ribosomes showed an enhancement of [3H]-phenylalanine incorporation of 20% and 54% respectively in controls, and of 32% and 45% respectively in uraemic rats. This study may rule out the influence of acute uraemia on protein synthesis capacity of isolated ribosomes and emphasize the importance of intracellular amino acid availability in altered protein synthesis.

CHANGES OF TAURINE METABOLISM IN ACUTE UREMIA

Taurine(Tau) is known to be important for the regulation of ion fluxes in excitable tissues,especially in the heart muscle,where it is the most abundant amino acid Neuromuscular disturbances are common in uremia.In order to investigate the role of Tau in uremia the concentration of Tau was determined in plasma, liver, brain,skeletal and heart muscle of 38 rats 12,24 and 48 hours after bilateral nephrectomy(NX) and compared with sham operated (SH) and normal animals. In NX rats mean plasma creatinine rose linearly from 0.44 to 7.39 mg/dl. Tau was found to be elevated in plasma with a maximum level of 0.41 vs. 0.23 μmol/ml at 24 hrs, and in liver, in which the highest level (7.2 vs. 2.0 μmol/g wet wt) was observed 48 hrs. post NX. Mean Tau concentration was unchanged in brain (5.3 μmol/g wet wt)and skeletal muscle (15.1 μmol/g wet wt), but was lowered in the heart(20.9 vs. 26.0 μmol/g wet wt). The decrease of heart Tau content was significantly correlated to the degree of uremia (p<0.001) and was not due to changes in heart weight, which was identical in NX and SH rats. In conclusion,the elevation of plasma and liver Tau concentration in acute uremia is not followed by similar changes in muscle and brain. The apparent efflux from the heart might be involved in the development of uremic heart disease.

Effect of somatotropin(STH), parathyroid hormone (PTH) and calcitonin (CT) on cAMP-content of growth cartilage in uremia

Retardation of growth is a well known feature in uremic children. There is considerable evidence that several hormone systems,which play an important role in normal growth,e.g. STH,PTH are altered in uremia. Adenylate cyclase mediates the action of most of these hormones on cell proliferation in the chondrocytes. The effects of STH,PTH and CT on cAMP content of cartilage was investigated. Methods:Male Wistar rats(60gBW)were bilaterally nephretomized(NX)or sham-operated(SO)24h before sacrifice. Bovine STH(6h),PTH and CT(15min) was given i.v. cAMP in cartilage was measured by RIA. Results: Basal cAMP content in cartilage was not different between NX and SO. Stimulation with 40IU i.v. PTH caused a significantly(p 0.01)lower cAMP increment in NX(11.4±1.0;SEM; n=20)than in SO(24.0±2.6).CT(2.5U)administration resulted in higher cAMP in NX(23.8±1.8;n=19)vs. SO(16.6±1.6). STH(0.1-5.14)was without effect on cAMP in NX or SO,but enhanced 3Thymidine incorporation. Discussion: Target organ resistance to PTH seems to be reflected by diminished cAMP response in uremic growth cartilage. CT has the opposite effect on NX.In the above model,with the dose of STH used,no effect on cAMP could be seen. Our present results provide evidence that in acute uremia the cAMP system may be involved in the growth abnormality of RF.

Carbohydrate metabolism and uraemia-mechanisms for glycogenolysis and gluconeogenesis.

Disturbances of carbohydrate metabolism during acute uraemia are characterized by the degradation of liver and muscle glycogen with a simultaneous activation of hepatic gluconeogenesis. After binephrectomy, the substitution of essential amino acids and keto analogues stimulate liver, but not skeletal muscle glycogen synthesis. Serine proves to be an optimal substrate for liver gluconeogenesis and muscle glycogen generation under acute uraemic conditions. Propranolol does not influence glycogenolysis of skeletal muscle in acutely uraemic rats. During starvation, acute uraemia leads to an increase of total carbohydrate content as well as of glycogen and glucose concentrations in heart muscle Alterations in carbohydrate contents are not observed in the kidney after ureter ligation. Enhanced glycogenolysis of skeletal muscle and liver during acute uraemia may be due to activation of phosphorylase kinase caused by the increased serum concentrations of various hormones (glucagon, catecholamines, parathormone) as well as free proteolytic activity, an increase of intracellular Ca2+-concentration and finally by alterations in the structure of contractile proteins.

Effects of high doses of leucine and ketoleucine on glycogen and protein metabolism in acute uremia

Binephrectomized rats treated with high doses of ketoleucine (0.5 g/rat per 20 hr) expired after about 45 hr. In contrast, survival time was 100% 60 hr after ureteral ligation. In comparison to animals receiving low-protein diets, addition of leucine to the diet almost doubled muscle and liver protein content whereas ketoleucine increased liver protein during the first 40 hr after operation about 1.5-fold. Skeletal muscle protein content was enhanced in the ureter-ligated rats with administration of ketoleucine. There was also about a 10-fold elevation in liver glycogen and total carbohydrate content between the 20th and 60th hr in binephrectomized rats fed leucine at 5-hr intervals. In skeletal muscle glycogen, there were no significant differences among the acutely uremic rats fed at 10-hr intervals low-protein diets alone or supplemented with leucine or ketoleucine. Leucine inhibits glycogenolysis by lowering phosphorylase alpha activity in muscle and liver, whereas ketoleucine enhances glycogenolysis in acute uremia. In rats supplemented with letoleucine, there is a progressive inactivation of glycogen synthetase I which occurs in parallel with increasing phosphorylase alpha activity. In binephrectomized rats receiving leucine supplements at 5-hr feeding intervals, the activity of liver glycogen synthetase I increases up to a maximum of 90% of total enzyme activity.

Glycogen metabolism in muscle in uremia

The effect of surgical trauma or acute uremia on glycogen metabolism of skeletal muscle was investigated in bilaterally nephrectomized and sham-operated rats. Glycogen content was decreased due to enhanced glycogenolysis (as determined by increased activation of phos- phorylase a 20 and 40 hr after operation) and decreased glycogen synthesis (glycogen synthetase I activity in fasting rats was only about 10% at 20 and 40 hr after operation as compared with control rats). In skeletal muscle of I-strain (phosphorylase kinase deficient) mice, glycogen concentration was 5-fold higher compared with control mice or rats. In contrast to the very low muscle glycogen content in skeletal muscle of acutely uremic fasting rats there was no decrease in muscle glycogen in fasting I-strain mice 8 or 24 hr after bilateral nephrectomy or sham operation, respectively. This indicates a key role for phosphorylase kinase in the pathogenesis of glycogen depletion in acute uremia or in postoperative stress. The feeding of large amounts of serine in combination with a high-calorie, mixed low-protein diet maximally stimulates glycogen synthesis in rat skeletal muscle. In agreement with . these findings, we were able to isolate a protein glycogen complex from rat skeletal muscle 60 hr after bilateral nephrectomy in serine treated animals. Due to a lower phosphorylase a activity in these animals (30%) as compared to nonserine treated rats (70%), flash activation of this enzyme could be induced in the presence of Ca�, � and ATP. Am. J. Cliii. Nut,. 33: 1461-1467, 1980. Studies by Bergstrom and Hultman (1) revealed a substantial decline (60 to 70%) in muscle glycogen stores in patients with acute renal failure. This phenomenon was indepen- dent of the cause of acute renal failure, but its magnitude was highest in patients with postsurgical acute uremia. A comparable low- ering of muscle glycogen was recorded by the same authors in the postoperative course of nonuremic surgical patients (2). In contrast, normal glycogen content was observed in patients with chronic renal failure with serum creatinine levels up to 25 mg/dl (1). In chronic uremic rats (90% nephrectomy) with a mean blood urea nitrogen of 105 mg/dl, the muscle glycogen stores are also normal (3). In addition, these rats had a 3-fold increase of the cyclic AMP dependent protein kinase and doubling of the phosphorylase a activity as compared to sham-operated animals. Simi- larby, the active I-form ofglycogen synthetase was significantly increased. These findings are consistent with an enhanced glycogen turnover in skeletal muscle of chronic uremic rats (3).