Acute Uremia Research Articles

Mechanisms causing loss of muscle in acute uremia.

The mortality of acute renal failure (ARF) remains high because most illnesses associated with ARF also cause loss of muscle mass. The mechanisms causing loss of muscle mass are inhibition of protein synthesis and/or acceleration of protein degradation. Identifying which of these abnormalities is present requires understanding the principles of amino acid and protein turnover. There is evidence that ARF by itself impairs protein synthesis and stimulates protein degradation. The mechanisms causing these defects include abnormal metabolic responses to hormones and stimulation of the ATP--ubiquitin--proteasome-dependent pathway. Understanding these mechanisms could lead to rational therapies.

Nutritional Aspects in Patients with Acute Renal Failure/ Multiorgan Failure

Nutrition support contributes to reducing morbidity and mortality in patients with the multiple-organ dysfunction syndrome (MODS). In cases when acute renal failure is a component of MODS, the goals of nutritional management should be to control general nutrient deficiencies and correct specific metabolic alterations caused by the loss of renal function or acute uraemia without worsening uraemic toxicity or disturbing electrolyte balance. In most cases energy requirements, which should ideally be estimated by indirect calorimetric measurements, amount to 30 kcal/kg/day and only seldom exceed 35 kcal/kg/day. Depending on the degree of protein catabolism, 1.0-1.5 g/kg/day of protein should be given. A balanced amino acid solution containing both essential and nonessential amino acids should be administered. Uraemia impairs protein synthesis and nitrogen administration should, therefore, not be started until the uraemic state is adequately controlled by dialysis or haemofiltration.

Is parenteral nutrition therapy of value in acute renal failure patients?

A patient with oliguric acute renal failure (ARF) following mitral valve surgery is presented. The patient was treated with parenteral nutrition and hemodialysis. While the patient survived, there were several complications of nutrition therapy. In this review, the benefits, risks, and uncertainties regarding parenteral nutrition in ARF are considered. First, the differences in metabolism in complicated and uncomplicated acute uremia are discussed. The important roles of alterations in intermediary metabolism and of proteases in the catabolism of ARF are emphasized. The historical basis of parenteral nutrition treatment in ARF is reviewed. The results are divided regarding the relationship among nutritional support, improvement in renal function, and enhanced patient survival. A critical analysis of nitrogen metabolism results reported in the literature does not convincingly support the effectiveness of parenteral nutrition formulae in generating positive nitrogen balance. The complications of parenteral nutrition therapy are outlined. In light of the uncertain efficacy and recognized risks of prolonged parenteral nutrition, a rationale for approaching therapy is presented that is based on the estimated metabolic stress and protein-energy requirements of the individual ARF patient.

Mifepristone (RU 486)

The antiprogestin RU 486 converts the early pregnant uterus by increasing the sensitivity of the myometrium to prostaglandin (PG). These effects of antiprogestin have resulted in the development of nonsurgical procedures to abort embryos based on a combination of RU 486 and different PG-analogues administered vaginally or intramuscularly. RU 486 also has a softening effect on the cervix which may be used as pretreatment in second and third trimester abortions. The effects, mode of action, dangers, and the many other postulated clinical implications (like breast cancer, meningioma, ectopic pregnancy, fetal death in utero, induction of labour, initiation and promotion of lactation, endometrial or ovarian cancers, leukemia, Cushing's syndrome, uterine adenomyosis, acute uremia, leiomyosarcoma, hypertension, etc.) are discussed.

Somatomedin C (IGF I) plasma levels after orthotopic liver transplantation (OLT) in end-stage cirrhotic patients.

Insulin-like growth factors [IGF I and II or somatomedins (SMS)] are polypeptides chemically and biologically correlated with insulin. The main source of synthetic activity and secretion is the liver, although many other tissues have been demonstrated to synthesize SMS. In the circulation, they are not present in a free form, but are mostly bound to a specific carrier protein independently synthesized in the liver. Hepatic or extrahepatic storage organs have not been demonstrated; the half life of the SMS-binding protein complex is between 3 and 4. Synthesis of SMS is regulated by GH, insulin, thyroxine and nutrition (caloric and protein intake, and nitrogen balance). The role of corticosteroids is still a matter of debate: in patients treated with steroids SMS blood levels have been shown to be within normal limits, while biological activity has been demonstrated to be significantly reduced by SMS inhibitors, probably induced by corticosteroid therapy. The biological properties of SMS are related to their structural homology with insulin, and can be summarized as follows: A. Insulin-like activity (glucose oxidation, lipogenesis, glycogen synthesis, inhibition of lipolysis and glycogenolysis); B. Sulphation activity (incorporation of sulphate and leucine into glycosaminglycans of the cartilage); C. Stimulation of fibroblast multiplication; D. Amplification of other hormone activities (GH); E. Complementary anabolic activity with insulin. Low levels of SMS have been demonstrated in hypopituitarism (secondary) or in other diseases independent of GH reduced secretion (primary) such as malnutrition, malabsorption, acute or chronic liver failure and uraemia. Negative nitrogen balance, hypocaloric and/or low protein diets are usually correlated with low levels of SMS. Recently, Schalch et al. reported on the role of orthotopic liver transplantation (OLT) in normalizing SMS blood levels in a group of end-stage liver diseased patients. This preliminary paper deals with changes in IGF-I plasma levels (somatomedin C) in a group of patients affected by end-stage liver cirrhosis before and after OLT.

Hepatic uptake and release of glucose, lactate, and amino acids in acutely uremic dogs

This study evaluated the potential contribution of the liver to glucose intolerance and insulin resistance in acute uremia. Eight bilaterally nephrectomized dogs and eight sham-operated dogs were studied, while awake, 24 to 30 hours after surgery. Blood levels and hepatic balance of glucose, lactate, and amino acids were measured during a baseline period and during a 90-minute infusion of glucose and insulin that maintained plasma glucose at 9 to 10 mmol/L. During the basal state, the acutely uremic dogs, in comparison to control dogs, displayed decreased femoral artery plasma glucose, whole blood total amino acids, and elevated blood lactate. In the liver of the uremic dogs, there was lower glucose output, less uptake of alanine, greater uptake of glutamine, and similar uptake of lactate, as compared with controls during the basal state. In the control dogs during the hyperglycemic clamp, the liver took up glucose and released lactate; the hepatic uptake of alanine diminished, and the hepatic output of glutamine persisted. In contrast, during the hyperglycemic clamp in the uremic dogs, there was no hepatic uptake of glucose; the hepatic uptake of alanine, glutamine, and lactate persisted, and the hepatic uptake of total amino acids was greater than in controls. Peripheral glucose uptake was also impaired in the acutely uremic dogs. Moreover, the uremic dogs had insulin resistance, as indicated by a low ratio of the glucose infusion rate of the plasma insulin levels, and a higher urea nitrogen appearance. Thus, acutely uremic dogs have altered hepatic handling of glucose and its precursors, which only becomes evident during a glucose load. When these animals receive glucose (and insulin) and become hyperglycemic (a common event in patients with acute renal failure), the liver and the periphery fail to dispose of glucose normally. Both of these factors may contribute to glucose intolerance and insulin resistance in acute uremia.

Small Intestinal Peptidases and Disaccharidases in Rats with Acute Uremia

Acute uremia was induced in rats with temporary clamping of the left renal pedicle and contralateral nephrectomy. Jejunal peptidase activities (aminopeptidase N, dipeptidyl peptidase IV and aminopeptidase A), disaccharidase activities (maltase, sucrase, lactase and trehalase) and morphology were studied. A significant (p less than 0.05) increase in aminopeptidase N activity and a positive correlation between aminopeptidase N activity and serum urea was found in the uremic rats. The other peptidase activities showed a slight increase in the uremic rats. A shortening of the microvilli of the small intestinal epithelial cells in the uremic rats was seen by electron microscopy. The disaccharidase activities was unaltered. This study shows the presence of functional alterations in the small intestine in rats with acute uremia. The observations are also compatible with different regulation mechanisms for the brush border peptidases and disaccharidases.

Effects of acute and chronic uremia on active cation transport in rat myocardium

As abnormalities of active cation transport could contribute to the genesis of uremic cardiomyopathy, we investigated myocardial sodium pump function in rats with acute renal failure (ARF) and with a model of experimental chronic renal failure (CRF) that has metabolic similarities to advanced chronic uremia in humans. CRF rats were hypertensive and had left ventricular hypertrophy (33% higher heart:body weight ratio; P less than 0.01) at four weeks compared to pair-fed sham-operated rats. Importantly, both ouabain- and furosemide-sensitive 86Rb uptake rates were unchanged in left ventricular myocardial slices from CRF, and the intracellular sodium concentration was not different from that of control rats even though skeletal muscle sodium was increased, as we found previously (J Clin Invest 81:1197, 1988). Insulin-stimulated, ouabain-sensitive 86Rb influx was also preserved. There also were no abnormalities in myocardium cation transport in rats with ARF. However, [3H]ouabain binding was decreased 45% in CRF rats (P less than 0.01); it was unchanged in acute uremia. Decreased ouabain binding in chronic uremia was due entirely to fewer low affinity [3H]ouabain binding sites (the binding affinity for ouabain was unaffected). We conclude that in chronic, (but not acute) renal failure, sodium pump number is reduced in myocardium but intracellular sodium is unchanged and active cation flux rates are maintained. These results emphasize that in rats with chronic uremia, intracellular sodium homeostasis is preserved in myocardium, despite the presence of marked abnormalities of active cation transport in skeletal muscle that are characteristic of chronic uremia.

Kinetics of system A amino acid uptake by muscle: effects of insulin and acute uremia

We found that acute renal failure (ARF) depresses maximal responsiveness to insulin of system A amino acid transport in muscle [Maroni, Karapanos, and Mitch. Am. J. Physiol. 251 (Renal Fluid Electrolyte Physiol. 20): F74-F80, 1986]. To examine mechanisms for this change, we measured the kinetics of system A in response to insulin and ARF in epitrochlearis muscle. Insulin stimulation increased the diffusion constant (KD) approximately twofold in muscles from both ARF and control rats, suggesting that insulin can modulate nonsaturable alpha-(methylamino)isobutyrate uptake. Compared with basal values, insulin did not significantly change maximal transport velocity (Vmax) in ARF or control rats; however, insulin decreased Michaelis constant (Km) by 79 and 63%, respectively. Inhibition of protein synthesis with cycloheximide did not prevent stimulation of system A by insulin. Acute uremia had no effect on nonsaturable uptake or basal system A kinetics. However, ARF produced opposing effects on insulin-stimulated system A kinetics. There was a approximately 47% decrease in Vmax, which was partially offset by a 66% reduction in Km. In summary, both insulin and ARF modulate system A kinetics by mechanisms that are independent of protein synthesis.

Normalization of enhanced hepatic gluconeogenesis by the antiglucocorticoid RU 38486 in acutely uraemic rats

Hepatic amino acid uptake, urea and glucose production are increased in acute uraemia. It has been shown that this metabolic pattern is mediated by glucocorticoids. Accordingly, the administration of the antiglucocorticoid RU 38486 to acutely uraemic rats resulted in a reduction of serum urea-N and glucose levels. To clarify whether this effect is due to a reduction in hepatic gluconeogenesis we examined the effect of the antiglucocorticoid RU 38486 on urea and glucose formation in isolated hepatocytes from sham-operated (SHAM) and bilaterally nephrectomized (BNX) rats receiving RU 38486 or the vehicle only. Hepatic glucose production in BNX rats was considerably increased from Na-pyruvate (+79%), alanine (+174%), glutamine (+158%), and serine (+87%) compared with SHAM animals. Concomitantly, hepatic urea formation was also enhanced from amino acid substrates in acutely uraemic rats. When uraemic animals were treated with RU 38486, glucose production from amino acids and Na-pyruvate was reduced to the range of SHAM animals or even lower. This effect could not be demonstrated in SHAM-operated controls. A comparable decrement in hepatic urea production was observed in BNX rats treated with the antiglucocorticoid. Thus, glucocorticoids appear to play a key role in the abnormal hepatic urea and glucose production of acutely uraemic rats.

Continuous high volume venous-venous haemofiltration in acute renal failure.

Continuous, high volume, venous-venous haemofiltration was used as renal support in 28 critically ill patients with acute renal failure. Fifteen patients survived and were subsequently discharged from the ITU. Although haemofiltration was highly effective in reducing the blood urea and serum creatinine, only survivors demonstrated a significant increase in arterial pH (medians before and at two days 7.28 and 7.49 respectively, p less than 0.005) with a reduction in severity of their illness (median APACHE II scores before and at two days 23 and 16, p less than 0.005). Patients who died remained severely ill and acidotic (median APACHE II scores before and at two days 26 and 28; median arterial pH values 7.32 and 7.31 respectively) and by day two of treatment, marked differences between the patient groups in APACHE II scores, mean arterial pressure, arterial pH and urine flow rate had developed. Haemofiltration with the correction of acute uraemia alone does not necessarily lead to a reduction in the severity of illness which in the critically ill more frequently reflects other organ dysfunction.

Somatosensory evoked potentials in rats with acute uremia.

The effects of acute renal failure (ARF) on somatosensory evoked potentials (SEPs) were studied in rats. With the increase in blood urea nitrogen caused by the ligation of bilateral ureters, both a significant augmentation of amplitudes of the SEP and an increase in the SEP latencies were observed. The nerve conduction velocities of peripheral nerves were unchanged. Thus a kind of cortical irritability and a lesser degree of damage in the peripheral nervous system are characteristics in ARF.

Functional changes in the inner ear in renal insufficiency. An experimental study in the rat.

In acute uremia the auditory brainstem response thresholds in the rat (n = 10) became primarily affected in the low-frequency area. As time elapsed in uremia, even the high-frequency thresholds became impaired. In most animals the latencies for wave 2 at the threshold level increased during the first 48 h concomitant with the impairment of thresholds. After 72 h of uremia, the latencies were shortened as compared with the control values.

Increased muscle glycogen-glucose-1-phosphate cycling in acute uraemia in the rat

Increased muscle glycogen-glucose-1-phosphate cycling in acute uraemia in the rat

Enzyme cytochemistry of rat organs after uremia with special reference to proteases.

Wistar rat organs and tissues were investigated after acute and chronic uremia using enzyme cytochemical means whereby special attention was paid to plasma membrane and lysosomal proteases. Heart muscle, pancreas, spleen, stomach, duodenum, jejunum, colon and skeletal muscle did not show any clear-cut indications of alterations. After acute uremia activities of dipeptidyl peptidase IV, glutamyl aminopeptidase and microsomal alanyl aminopeptidase were decreased in the extraorbital gland and that of dipeptidyl peptidase IV in the submandibular gland. The thymus showed an increased staining for glutamyl aminopeptidase and lysosomal proteases. An activity increase of dipeptidyl peptidase IV, acid phosphatase and beta-N-acetyl-D-glucosaminidase occurred in bronchial lavage cells among which the alveolar macrophages predominated. In addition, their number was comparatively higher. Non-specific esterase activity was lowered in these cells. Alkaline phosphatase activity was drastically enhanced at the biliary pole of hepatocytes. Following chronic uremia all effects were less pronounced except for the lavage cells which were positive for glutamyl aminopeptidase, microsomal alanyl aminopeptidase and gamma-glutamyl transpeptidase and showed increased staining for lysosomal proteases, glycosidases and nonspecific phosphatases.

Prostaglandin synthetase inhibitors are not beneficial in the hypercatabolic state of acute uremia in rats.

In rats the effect of prostaglandin synthetase inhibition on the enhanced protein degradation in acute uremia was investigated. After 48 h of bilateral nephrectomy the urea nitrogen appearance, an indicator of net protein degradation, was calculated, and N tau-methylhistidine (N tau-MH) serum concentration was measured for judging myofibrillar breakdown. Also serum urea nitrogen, creatinine, and potassium serum concentrations were followed up. All bilateral nephrectomized rats showed severe uremic disturbances with increased (P less than 0.01) concentrations of serum urea nitrogen, creatinine, and potassium. Moreover, the urea nitrogen appearance and N tau-MH serum concentration increased (P less than 0.05) significantly. Administration of indomethacin (4 mg.kg-1b.wt./12 hi.p.) in bilateral nephrectomized rats did not influence the analyzed parameters significantly. Thus, we could not demonstrate a positive influence on the increased skeletal muscle degradation in acutely uremic rats by prostaglandin synthetase inhibition. These data suggest that in our model of acute uremia prostaglandins do not play a major role in the degradation of striated muscle.

Reduction of urea generation and muscle protein degradation by adrenalectomy in acutely uremic rats.

The effect of adrenalectomy on the enhanced protein degradation in acute uremia was investigated. Therefore, serum urea nitrogen, urea N appearance and Nt-methylhistidine were followed in bilaterally nephrectomized rats. At 48 h after induction of uremia the animals displayed serum urea nitrogen levels of 223 +/- 9.5 mg/dl as compared to 26.0 +/- 1.0 mg/dl in sham-treated rats. This increment was significantly attenuated in acutely uremic, adrenalectomized animals (176 +/- 6.0 mg/dl). When these rats were substituted with corticosterone (5 mg/kg body weight), serum urea nitrogen readily increased to levels of acutely uremic animals with intact adrenal glands (225 +/- 6.0 mg/dl). The net generation of urea, as determined by the urea N appearance, was significantly increased during acute uremia (370 +/- 26 mg/48 h) as compared to SHAM animals (220 +/- 15 mg/48 h). This increment of urea formation could almost be completely reversed by simultaneous adrenalectomy (238 +/- 20 mg/48 h). When these rats were substituted with corticosterone, the urea N appearance rebounded to values quite comparable to acutely uremic rats with intact adrenal glands (363 +/- 30 mg/48 h). To determine whether skeletal muscle proteins might serve as a source for the enhanced protein degradation in acute uremia, plasma levels of Nt-methylhistidine were measured. Bilaterally nephrectomized rats had Nt-methylhistidine values of 9.6 +/- 1.0 micrograms/ml. In acutely uremic rats without adrenal glands, Nt-methylhistidine levels were found to be significantly decreased (6.0 +/- 0.4 micrograms/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Sural nerve morphology in asymptomatic uremia.

This study evaluates morphologically the sural nerves of two patients with acute and another pair with chronic uremia, both of whom had neither clinical nor electrophysiologic evidence of neuropathy. Morphometric changes indicative of myelin repair were noted in the chronic uremic case who had a shorter duration of renal failure but required dialysis. Also, changes suggestive of axonal degeneration were found in the case who had chronic uremia of long duration. Both cases of acute uremia did not reveal significant abnormalities. Structural changes in the sural nerves may precede clinical and nerve conduction derangements in uremia, specifically in chronic cases.

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.