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PubMed1988

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.

Aminopeptidases↗
PubMed1998

Insulin, branched-chain amino acids, and growth failure in uremia.

Insulin and branched-chain amino acid (BCAA) metabolism was studied in 14 adolescents with uremia on hemodialysis. Glucose tolerance was measured by intravenous glucose tolerance tests. Insulin sensitivity was measured by the euglycemia clamp technique. Insulin secretion during constant hyperglycemia was measured by the hyperglycemic clamp technique. Fasting plasma BCAA concentrations were compared with data from 8 adolescent controls, whereas insulin indices were compared with 8 young adults controls and with published normal data in adolescents. The patients could be further sub-divided into two groups with respect to their growth velocity standard deviation score (GVSDS). Group 1 consisted of 7 patients with GVSDS less than -2. This group demonstrated insulin resistance, glucose intolerance, and low insulin secretion. This group also had low plasma valine, leucine, and isoleucine concentrations compared with control values. Group 2 consisted of 7 patients with GVSDS more than -2. This group demonstrated insulin resistance, but normal glucose tolerance and normal insulin secretion. Plasma valine, leucine, and isoleucine concentrations in group 2 were not different from control values. Total plasma BCAA correlated with glucose tolerance index and with insulin secretion, but not with insulin sensitivity. Growth failure in uremia is associated with glucose intolerance, hypoinsulinemia, and low plasma BCAA concentrations. Impaired utilization of conventional energy sources leading to preferential oxidation of BCAA may contribute to reduced anabolism and growth failure in uremia.

Adolescent↗
PubMed1983

Tyrosine supplementation in chronic experimental uremia.

The occurrence of low tyrosine tissue levels in uremic subjects, possibly due to impaired phenylalanine hydroxylation, suggests that tyrosine may be an essential amino acid in uremia. Additional dietary tyrosine may thus re-dress the deficiency. This study examined growth and tyrosine/phenylalanine metabolism in uremic rats during tyrosine supplementation. Rats made uremic (U) by 7/8 nephrectomy were compared to pair-fed (CP) and ad libitum-fed (CA), sham-operated controls. Two sets of each group of rats were studied after 21 days on the respective diets: I = Purina Lab Chow; II = same + 3.5% tyrosine. Plasma tyrosine was below normal in U and CP-fed diet I. With diet II, the tyrosine:phenylalanine ratio in U was lower than both CA and CP. In rats fed diet II, the tyrosine:phenylalanine ratio became indistinguishable among the three groups. Growth parameters in U and CP were similar, regardless of the diet. Body weight gain, tibial length, muscle mass, and tissue protein did not improve in uremic animals supplemented with tyrosine. The specific activity of liver phenylalanine hydroxylase in U was not different from CA or CP. However, loss of cortical renal mass appeared to be the major determinant of decreased kidney phenylalanine hydroxylation in experimental uremia. This alteration is likely to be the greatest contributory factor to the alteration of plasma levels of tyrosine and phenylalanine. The data presented do not support a proposed essentiality of tyrosine in uremia.

Animals↗
PubMed1982

Correction of drug binding defects in uremia in vitro by anion exchange resin treatment.

Serum protein binding of weakly acidic drugs is impaired in uremia, but that of basic drugs tends to be normal. Treatment of uremic serum with anion exchange resin (Amberlite CG-400, acetate form) corrected binding defects for three acidic drugs (nafcillin, salicylate and sulfamethoxazole) but did not affect the binding of two basic drugs (trimethoprim and quinidine). Resin treatment of normal human serum did not alter the binding of these five drugs. Extraction of the acetate buffer eluate from resin exposed to uremic serum with n-butyl chloride at acidic pH (3.0) resulted in a fraction that could induce similar binding defects in normal human serum. The factor(s) responsible for binding defects in uremia appears to be lipid soluble, weakly acidic, and dialyzable. It is believed to be tightly bound to albumin at physiologic pH, but dissociates from it at acidic pH. These findings further support the previously proposed hypothesis that drug-binding defects in uremia are due to accumulation of certain endogenous metabolic product(s).

Adult↗
PubMed1985

Plasma and brain catecholamines in experimental uremia: acute and chronic studies.

To evaluate the role of catecholamines (CA) in uremia, we used "high performance" liquid chromatographic technique with electrodetection to determine plasma and brain concentration of dopamine (DA), norepinephrine (NE) and epinephrine (E) in rats with acute and chronic uremia. The results revealed a steady elevation in plasma CA (p less than 0.05) in both acutely and chronically uremic rats when compared to the level of these neurotransmitters in controls. The highest changes were observed in DA and the least in NE (16.8 +/- 3.2 vs. 0.5 +/- 0.2 ng/ml and 93.2 +/- 11.1 vs. 68.1 +/- 16.3 ng/ml). There was a positive correlation between plasma CA and the duration of uremia (r = 0.97; p less than 0.05). The elevations were more pronounced in acutely uremic rats than in chronically uremic rats. This was followed by a concomitant depletion in the concentration of DA, NE and E in the brain. The defects in catecholaminergic neurotransmission as evidence of dysfunction in the autonomic nervous system may contribute to the development of neuropathy.

Acute Kidney Injury↗
PubMed1986

Insulin resistance in uremia: in vitro model in the rat liver using human serum to study mechanisms.

We have previously demonstrated in a rat model of chronic uremia that the liver is resistant to insulin. To further investigate the mechanism(s) of insulin resistance in uremia, primary cultures of normal rat hepatocytes were incubated with varying dilutions (1/10 to 1/10,000) of sera from undialyzed end stage uremic and normal humans for 20 hours. We then studied insulin action, binding, and postbinding events. Dilutions of uremic sera as low as 1/1,000 rendered the hepatocytes resistant to maximal concentrations of insulin with regard to [14C]acetate incorporation into lipids. The dose response curve for insulin-stimulated [14C]aminoisobutyric acid uptake demonstrated a shift to the right in hepatocytes incubated with uremic sera when compared with those incubated with normal sera. The 125I-insulin binding sites and affinity, 125I-insulin internalization and degradation, insulin receptor structure, autophosphorylation of the insulin receptor, and its tyrosine-specific kinase activity were normal in the hepatocytes rendered resistant to insulin by uremic sera. However, these cells failed to generate the chemical mediator or second messenger of insulin action, as assessed by its ability to stimulate pyruvate dehydrogenase (PDH) in liver mitochondria from normal rats. We concluded that uremic sera renders normal rat hepatocytes resistant to insulin. Insulin resistance is a postinsulin receptor kinase defect possibly due to lack of the generation of the chemical mediator of insulin action. This in vitro cell model may be useful to further define the mechanism(s) and the serum factor(s) responsible for insulin resistance in uremia in the absence of complicating hormonal and substrate changes that occur in vivo.

Adult↗
PubMed1990

Altered monocyte function in uremia.

Uremia appears to suppress immune function predisposing patients to infections. When the defect in cellular immunity was studied by exposing mononuclear cells (MNC) from uremic patients and controls to tetanus toxoid, diptheria toxoid, or Candida albicans antigen in vitro, the uremic cells were far less responsive. Monocytes and T cells, which are both involved in the proliferative response to soluble antigens, were isolated from MNC of uremic patients and HLA class II matched controls and incubated with tetanus toxoid. Tetanus toxoid-pulsed uremic monocytes were unable to stimulate the proliferation of HLA identical control T lymphocytes. Lymphocytes from uremic patients, however, were stimulated by tetanus toxoid-pulsed control monocytes. Therefore, the ability of monocytes to function as accessory cells is severely affected by uremia. The uremic monocytes were FcR+, produced IL-1 beta, and expressed levels of HLA class II antigens comparable to controls. Although the biochemical defect in uremic monocytes remains unknown, the abnormality could explain many of the immunological changes of uremia.

Adolescent↗
PubMed1995

Changes of vascular architecture independent of blood pressure in experimental uremia.

Striking alterations of the structure of arterial vessels of different caliber are a well-known feature of renal failure, but it is currently unknown to what extent they are a reflection of hypertension or of uremia per se. To address this issue further we studied subtotally nephrectomized rats, sham-operated and pair-fed with matched controls. After uremia of 14 days' duration, stereologic measurements were carried out on perfusion-fixed tissue. To eliminate a potential influence of hypertension, subgroups of animals received furosemide and hydralazine in the drinking fluid to yield daily doses of 15 mg/kg and 20 mg/kg, respectively. At the end of the experiment, systolic blood pressure (tail plethysmography) was 110 +/- 13.3 (mean +/- SD) mm Hg and 99.4 +/- 8.1 mm Hg in untreated and treated controls, respectively, and 132 +/- 20.7 mm Hg and 103 +/- 13.0 mm Hg in untreated and treated uremic animals, respectively (n = 5 to 10 animals per group). The wall:lumen ratio of intramyocardial small arteries was 0.056 +/- 0.011 and 0.052 +/- 0.006 in untreated and treated controls, respectively. In untreated and treated uremic animals, the corresponding values were 0.077 +/- 0.011 and 0.066 +/- 0.007 (P < .01; control v uremia, ANOVA). A similar increase, unaffected by blood pressure treatment, was found for wall thickness of intramyocardial arteries. Analogous changes were also noted in mesenteric arterioles and veins. Finally, aorta media thickness was significantly (P < .005) higher in uremic animals than in controls (138 +/- 29 micrometers v 103 +/- micrometers).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Chronic systemic inflammation in uremia: potential therapeutic approaches.

Systemic inflammation characterizes several chronic diseases including uremia. Inflammation may contribute to morbidity and mortality by enhancing protein-calorie malnutrition, infectious complications, and atherosclerosis and cardiovascular disease. Although inflammation in renal disease can be caused, at least in part, by reduced renal clearance of proinflammatory mediators (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6), several pathogenetic mechanisms are likely to contribute to direct activation of the inflammatory process under these conditions. These mechanisms include accumulation of advance glycoxidation end products, production of reactive oxygen species and oxidative damage, and chronic infection. Support for direct activation of systemic inflammation provides a strong rationale for use of anti-inflammatory treatments in uremia. The current article describes the association between uremia and inflammation, provides evidence for activation of inflammatory process, and provides potential therapeutic approaches.

Chronic Disease↗
PubMed2005

Bladder cancer with obstructive uremia: oncologic outcome after definitive surgical management.

OBJECTIVES: To report the surgical and oncologic outcomes of patients with bladder cancer who present with obstructive uremia. METHODS: A total of 61 patients presented to our institute with obstructive oliguria or anuria concomitant with bladder cancer. The mean serum creatinine at presentation was 11.4 +/- 5.1 mg%. After stabilization of kidney function following nephrostomy drainage, only 38 patients were eligible for radical cystectomy. Analysis of the intraoperative findings, early postoperative course, definitive histopathologic findings, and long-term functional and oncologic outcome was performed. The mean follow-up period was 16.2 +/- 8.1 months (range 8 to 134). RESULTS: Radical cystectomy with bilateral iliac lymphadenectomy was feasible in 26 patients, palliative cystectomy in 10, and ileal conduit only without cystectomy in 2. The postoperative morbidity was minimal and treated conservatively. Bladder cancer causing uremia was invasive in 94.5%, and was pathologic Stage T4 in 30.5% of cases. At the mean follow-up, treatment failure was observed in 26 patients (68.4%), with only 12 patients living free of disease and a mean serum creatinine of 1.4 +/- 0.7 mg%. Although none of the preoperative variables proved to be predictive of the oncologic outcome, significant correlation was found between the tumor stage and grade, as well as lymph node involvement, and treatment failure. CONCLUSIONS: Although bladder cancer causing obstructive uremia is almost always muscle invasive, with a large proportion of patients presenting with locally advanced disease, an adequate number of these patients could achieve long-term disease-free survival.

Adult↗
PubMed1978

Pathogenesis of glucose intolerance in uremia.

The pathogenesis of glucose intolerance in uremia was examined with the glucose clamp technique. Hyperglycemic clamp (n = 8): The plasma glucose concentration is acutely raised and maintained at 125 mg/dl above basal levels. Under these steady state conditions the glucose infusion rate, M, equals the amount of glucose metabolized: Predialysis M averaged 4.23 +/- 0.36 mg/kg/min and increased to 7.71 +/- 0.43 postdialysis (p less than 0.001). The plasma insulin response predialysis was 90 +/- 20 microU/ml and decreased to 80 +/- 23 microU/ml following dialysis. Consequently the M/l ratio, a measure of tissue sensitivity to insulin, increased by 80% +/- 25% (p less than 0.001) but still remained less than controls (p less than 0.01). Euglycemic insulin clamp (n = 10): The plasma insulin concentration is acutely raised by 100 microU/ml and the plasma glucose concentration is held constant at the basal level. Predialysis both M (3.37 +/- 0.36 mg/kg/min) and M/l (3.56 +/- 0.33 mg/kg/min per microU/ml X 100) were significantly less than controls (p less than 0.01). Postdialysis both M and M/l increased significantly (p less than 0.01) to a mean that was not significantly different from controls. Basal hepatic glucose production (n = 6), 2.15 +/- 0.09 mg/kg/min, was similar to controls and fell (87% +/- 4%) normally during the insulin clamp. In five uremic subjects in wom insulin binding to monocytes was measured, there was no correlation with tissue sensitivity to insulin (M/l). Significant abnormalities in both growth hormone and glucagon physiology were present in uremic individuals, but no correlation with either the presence or degree of glucose intolerance was demonstrable. In conclusion, glucose intolerance is universally present in uremic subjects and results primarily from peripheral tissue insensitivity to insulin. Insulin secretion is usually enhanced in an attempt to compensate for this insulin resistance but in occasional subjects uremia also inhibits beta cell sensitivity to glucose. Hepatic glucose production is unaffected by uremia. The lack of correlation between insulin binding and tissue sensitivity to insulin suggests that the cellular mechanism accounting for the insulin resistance is probably the result of a defect in intracellular metabolism or in the glucose transport system.

Adult↗
PubMed1996

Managing gastrointestinal complications of uremia.

Dogs and cats with uremia may display abnormalities of essentially all parts of the gastrointestinal (GI) tract. Abnormalities may be mild or severe. They may result from inflammation, edema, erosions, ulceration, and/or necrosis. Clinical signs of GI complications or uremia may include anorexia, nausea, vomiting, abdominal pain, diarrhea, and GI bleeding. This article discusses the GI manifestations of uremia according to anatomic sites and also describes the management of common clinical problems as they relate to uremic GI abnormalities.

Animals↗
PubMed1994

Metabolic consequences of uremia: extending the concept of adaptive responses to protein metabolism.

An early response to metabolic acidosis is an increase in the degradation of muscle protein to provide the nitrogen needed to increase glutamine production so the kidney can excrete acid. In patients with renal insufficiency, this process may represent an example of a trade-off adaptation to uremia. It requires a hormone (glucocorticoids) and the metabolic response is maladaptive because the inability of the damaged kidney to maintain acid-base balance results in loss of muscle protein. Studies of cultured cells and rats and humans with normal kidneys demonstrate that acidosis stimulates the degradation of both amino acids and protein, which would block the normal adaptive responses to a low-protein diet (ie, to reduce the degradation of essential amino acids and protein). Evidence from studies in rats and humans with chronic uremia show that acidosis is a major stimulus for catabolism. The mechanism includes stimulation of specific pathways for the degradation of protein and amino acids. Since other catabolic conditions (eg, starvation) appear to stimulate the same pathways, understanding the mechanism in acidosis could be applicable to other conditions. Thus, the loss of lean body mass in uremia appears to be a consequence of a normal metabolic response that persists until acidosis is corrected.

Acidosis↗
PubMed1976

Skeletal resistance to the calcemic action of parathyroid hormone in uremia: role of 1,25 (OH)2 D3.

Studies were carried out to investigate the role of 1,25(OH)2D3 in the skeletal resistance to the calcemic action of parathyroid hormone. The change in serum calcium after the intravenous infusion of 2 U of parathyroid extract (PTE)/kg body wt/hr for eight hours was evaluated in thyroparathyroidectomized (T-PTX) dogs before, and one, two and three days after, induction of uremia by bilateral ureteral ligation (11 dogs) or by bilateral nephrectomy (8 dogs). In another six nephrectomized and T-PTX dogs, 0.68 ug of 1, 25 (OH)2D3/day was given on the day of nephrectomy and for two days thereafter. Serum creatinine in each day of the study was not different among the three groups. The study also included the evaluation of the effect of sham operation (five dogs) and the administration of 1,25 (OH)2D3 to dogs with normal renal function (four dogs) on the calcemic response to PTE, as well as the reproducibility of such a response in the same animal. The results showed that 1) the calcemic response to PTE was markedly impaired after one day of bilateral ureteral ligation or nephrectomy, but the impairment was more severe after nephrectomy; 2) the calcemic response to PTE after two or three days of bilateral ureteral ligation was similar to that seen at one day after nephrectomy; 3) 1, 25 (OH)2D3 partially restored the calcemic response to PTE in the nephrectomized animals to levels similar to those seen after one day of bilateral ureteral ligation; 4) sham operation did not affect the response to PTE, and repeated infusion of PTE produced similar changes in the concentrations of serum calcium. The data indicate that (a) a deficiency of 1,25 (OH)2D3 is at least partly responsible for the skeletal resistance to the calcemic action of PTH in uremia; (b) uremia, per se, may also contribute to this phenomenon; and (c) the kidney after one day of complete bilateral ureteral ligation may still produce 1,25 (OH)2D3, but this ability is compromised after two days of ureteral obstruction.

Animals↗
PubMed1977

Effect of uremia on nutritionally-induced variations in protein metabolism.

The effect of uremia on nutritionally-induced variations in protein metabolism was studied in growing rats with chronic, moderate uremia. Plasma and muscle protein synthetic activities and related values were measured from incorporation rates of 14C-leucine infused over a six-hour period. Synthetic activities were compared in the postabsorptive (2 to 14 hr after feeding) and in the fasting (18 to 24 hr after feeding) states. Differences between uremic and control rats were seen in fasting: plasma and intracellular leucine declined in control rats as fasting developed; they rose in uremic rats. In fasting uremic rats, a smaller percent of leucine efflux from extracellular fluid was used for protein synthesis. In a second study, muscle protein synthesis (Sm) and net urea nitrogen production (UNPr) were compared between control and uremic rats which were a) food-deprived but given carbohydrate for 36 hr, and b) fasted for 36 hr. Fasting, as contrasted with carbohydrate feeding, was associated with depressed muscle protein synthesis and increased UNPr in both control and uremic rats; the changes were greater in uremic rats. We conclude that food deprivation for more than 14 hr incurred greater catabolic responses of body protein in moderately uremic rats. The effect was mediated in part by greater suppression of muscle protein synthesis. In contrast, moderate uremia had little discernible effect upon protein metabolism in the postabsorptive state or food deprived state when gluconeogenesis was suppressed with glucose administration.

Alanine↗
PubMed1980

Plasma protein binding in uremia: extraction and characterization of an inhibitor.

The impairment of binding drugs and other substances to serum albumin in patients with uremia can be restored to normal or near normal levels by adsorption with charcoal or synthetic polymers at pH 3. We used a nonionic poly-styrene-divinylbenzene copolymer to treat uremic plasma at pH 3. We observed a marked improvement of binding. Subsequent elution of this resin with ethanol produced a substance that, when dried and recombined with normal plasma, caused dose-dependent impairment of phenytoin and tryptophan binding. Restoration of normal binding affinity occurred after retreatment of this abnormalized plasma with resin at pH 3. Plasma and pleural fluid exudate from patients with uremia yielded, after extraction by the above technique, and inhibitor(s) of phenytoin binding in amounts averaging five times that extracted from equal volumes of normal plasma. This inhibitor (IX) is water soluble, heat stable, and dialyzable across cellophane membranes. Unlike fatty acids, which can also interfere with binding, IX partitions primarily in the water phase in solvent partition studies but undergoes a sharp transition in th pH 4 to 5 range, suggesting the presence of carboxyl group. These findings lend further support to the hypothesis that a retained ligand(s) is responsible for impaired plasma binding associated with uremia and suggests a role for organic acids known to accumulate in renal failure.

Animals↗
PubMed1985

Effect of chronic uremia in the rat on cerebral mitochondrial calcium concentrations.

Whole cerebral and isolated mitochondrial calcium levels were determined in normal and chronically uremic Sprague-Dawley rats. Uremia was induced by a two-stage 5/6 nephrectomy 4 weeks prior to study. Serum was obtained for urea, calcium, magnesium, phosphate, and i-PTH. Mitochondria were isolated by gradient centrifugation and calcium was determined by flameless atomic absorption spectrophotometry. The results demonstrate that mitochondrial calcium levels in uremic rats are not different from normal (8.0 +/- 2.8 vs. 7.8 +/- 1.8 nmoles/mg protein) despite an 11% increase in whole cerebral calcium concentration (17.3 +/- 2.0 vs. 15.5 +/- 2.8 nmoles/mg protein; P less than 0.005) in 24 severely uremic rats (BUN greater than 18.0 mmoles/liter). Multiple regression analysis demonstrates a significant positive correlation between cerebral calcium concentrations and both serum calcium (P less than 0.005) and serum magnesium levels (P less than 0.005). No relationship was found for urea, serum phosphate, or i-PTH. Similar analysis of mitochondrial calcium concentration demonstrated a significant positive correlation with serum calcium (P less than 0.005) and i-PTH (P less than 0.05) suggesting that increased PTH may be necessary for maintaining normal intracellular calcium levels in uremia. We conclude that uremia in the rat is associated with a small rise in whole cerebral calcium but that intracellular calcium as reflected by mitochondrial levels is not elevated.

Animals↗
PubMed1988

Dose-effect and pharmacokinetics of estrogens given to correct bleeding time in uremia.

Conjugated estrogens have a significant and long-lasting effect in shortening bleeding time in patients with end-stage renal disease. The studies so far available indicate that repeated estrogen administrations are necessary to short bleeding time in uremia in a dose range of 95 to 325 mg. With the present study we wanted to establish whether single or repeated doses are required to induce a significant shortening of bleeding time in uremia, and the minimum cumulative dose of conjugated estrogens necessary to control bleeding time for a prolonged period of time, and to check whether the prolonged effect of estrogens on bleeding time in uremia is due to an accumulation of the drug or its metabolites in the blood. Fifteen uremics on chronic hemodialysis were studied. A pilot study carried out in five uremic patients indicated that single or repeated estrogen infusions of 0.3 mg/kg did not significantly influence bleeding time values. Therefore the subsequent studies have been carried out using daily infusion of 0.6 mg/kg. A single estrogen infusion of 0.6 mg/kg shortened bleeding time in all patients. The effect was transient and bleeding time returned to pre-infusion values within 72 hours. A 50% decrease of bleeding time or a shortening of bleeding time more than 30 to 15 minutes or less was obtained in all patients with four or five infusions (0.6 mg/kg) spaced 24 hours apart. The effect lasted for 14 days. At day 25 from the last infusion all the patients had bleeding time values comparable with the pre-infusion ones.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗