Acute Uremia Research Articles

Hyperparathyroidism and hypotestosteronemia of acute renal failure.

Acute and chronic renal failure are associated with a marked reduction in the serum levels of testosterone. The mechanisms underlying this abnormality are unknown. Certain data have implicated the high blood levels of parathyroid hormone (PTH) of uremia in the genesis of the hypotestosteronemia. The effects of 3 days of acute uremia in dogs with intact parathyroid glands and in thyroparathyroidectomized animals on serum testosterone levels and on the calcium content of the hypothalamus, pituitary gland, and the testes were examined. Similar studies were performed in normal dogs treated with parathyroid extract for 3 days. The serum levels of testosterone were significantly (p less than 0.01) reduced, and the calcium levels of hypothalamus, pituitary gland, and testes were significantly (p less than 0.01) increased in the acutely uremic dogs with intact parathyroid glands and in the normal dogs treated with parathyroid extract. Prior parathyroidectomy in the acutely uremic dogs prevented these abnormalities. The results of our study assign an important role for the excess blood levels of PTH in uremia in the genesis of the hypotestosteronemia. The data suggest that the effect of excess PTH on serum testosterone levels may be mediated through the accumulation of calcium in the organs which participate in synthesis and/or release of testosterone.

The effects of postoperative factors on serum thyroid hormones and rat liver nuclear 3,5,3'-triiodothyronine receptor concentrations in surgical models of uremia and regenerating liver.

We have determined the individual effects of postoperative fasting, surgical/anesthetic factors, acute uremia (AU), and regenerating liver (RL) on nucleoplasmic (NP; 0.15 M KCl-extractable) and chromatin-bound (CB; 0.4 M KCl-extractable) rat liver T3 receptors. AU and RL rats were studied 24 h after bilateral nephrectomy (blood urea nitrogen, 128 +/- 13 mg/dl) or two thirds hepatectomy, respectively. The effects of postoperative fasting were assessed by comparison of normal rats (N) with control rats (N6) pair-fed to match the caloric intake of the AU and RL rats. Surgical/anesthetic effects were determined by comparison of N6 rats with sham-operated pair-fed rats (S6). The effects of AU or RL were obtained by comparison with S6 controls. Changes in mean body weight attributable to fasting (N6-N), surgical/anesthetic effects (S6-N6), acute uremia (AU-S6), and regenerating liver (RL-S6) were: -17.3 (P less than 0.001), -4.0 (P = NS), -4.5 (P less than 0.05), and -1.0 g/24 h (P = NS), respectively. Changes in mean serum T4 (N, 5.3 +/- 1.3 micrograms/dl) were: -1.0 (P = NS), -0.6 (P = NS), -0.9 (P less than 0.05), and -1.0 micrograms/dl (P less than 0.05), respectively. Changes in mean serum T3 (N, 53 +/- 23 ng/dl) were: -8 (P = NS), -18 (P less than 0.05), -10 (P = NS), and -14 ng/dl (P less than 0.05), respectively. The NP and CB receptor pools of the AU and RL rats were not significantly different from those of age-matched N rats (NP, 25 +/- 5 fmol/mg DNA; CB, 405 +/- 134 fmol/mg DNA). Chronically uremic (CU) rats 2 weeks after five sixths nephrectomy (blood urea nitrogen, 36 +/- 2 mg/dl) did not exhibit significant change in their extractable receptor pools. Complete starvation for 24 h (NO) or 72 h (NOO) generally resulted in marked reductions in receptor concentrations compared to those in age-matched N rats fed ad libitum: NP pool (N, 31 +/- 17 fmol/mg DNA): NO-N, -40% (P = NS); NOO-N, -59% (P less than 0.01); CB pool (N, 303 +/- 105 fmol/mg DNA): NO-N, -19% (P less than 0.05); NOO-N, -41% (P less than 0.001). These studies indicate that severe AU, moderate CU, and LR have relatively little effect on solubilized rat liver nuclear receptor concentrations. In contrast, complete starvation is a potent depressant of both nuclear receptor pools. In the surgical models of AU and LR, postoperative fasting was the primary cause of weight loss.(ABSTRACT TRUNCATED AT 400 WORDS)

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)

The role of renal biopsy in acute renal failure.

There is agreement among the nephrologists that renal biopsy is of value for selected patients with acute uremia. It may be indicated for making or confirming a clinical diagnosis, to assess prognosis or to provide a basis for treatment.KeywordsAcute Renal FailureRenal BiopsyAcute Tubular NecrosisThrombotic MicroangiopathyMixed CryoglobulinemiaThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Glucose metabolism in acute renal failure.

Fasting hyperglycemia as well as a prolonged elevation of plasma glucose after both oral (OGTT) and intravenous glucose tolerance test (IVGTT) has been observed in acute uremic patients and in experimentally induced acute uremia in animals (1,2,3).KeywordsGlucose UptakeAcute Renal FailureGlucose OxidationHepatic Glucose ProductionUremic PatientThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

System A amino acid transport in incubated muscle: effects of insulin and acute uremia.

The insulin-stimulated increase in amino acid uptake in most cells and tissues involves stimulation of system A transport. In muscle the probes used to study this process have not been specific, making it difficult to determine whether system A is abnormal in insulin-resistant states, such as acute renal failure (ARF). To circumvent this problem, we studied 2-(methylamino) isobutyrate (MeAIB) transport. Its specificity for system A in incubated rat epitrochlearis muscles was documented by showing its uptake by only one carrier that is sodium dependent and insulin responsive and that exhibits adaptive regulation in response to starvation. Using this specific probe we determined whether insulin-stimulated amino acid transport by system A is impaired by ARF. MeAIB uptake was linear for 3 h in muscles of ARF and sham-operated (SO) rats. In the absence (basal) or presence of insulin, MeAIB uptake was significantly lower in ARF, yet the stimulation by insulin was similar in both groups. Likewise, the insulin dose-response relationship confirmed that physiological levels of insulin (less than or equal to 10(2) microU/ml) increased transport by a similar degree. At greater than or equal to 10(2) microU/ml insulin there was a plateau in MeAIB transport in ARF but not in SO muscles. Thus basal system A transport is depressed in ARF, but the stimulation of system A by physiological levels of insulin is preserved. At pharmacological levels of insulin system A transport is impaired by ARF.

System ASC and sodium-independent neutral amino acid transport in muscle of uremic rats.

Neutral amino acids are transported by systems A, ASC, and L. In the previous companion study we demonstrated that 2-(methylamino) isobutyrate (MeAIB) is a specific substrate for system A in muscle and that stimulation of system A by physiological concentrations of insulin is preserved in acute uremia (ARF). Insulin-stimulated uptake of the nonspecific probes cycloleucine and alpha-aminoisobutyrate (AIB) is reportedly blunted by uremia; the cause of this and whether transport by systems ASC and L is defective are unknown. In this study we examined these questions using incubated epitrochlearis muscles from normal fed, ARF, and sham-operated control (SO) rats. System ASC was studied by measuring AIB and cycloleucine uptake in the presence of inhibitors of systems A and L, MeAIB and 2-amino-2-norbornane carboxylic acid (BCH), respectively. System L was defined as sodium-independent uptake suppressible by BCH. Excess MeAIB completely inhibited insulin-stimulated AIB and cycloleucine uptake, indicating that system A is the only insulin-responsive neutral amino acid carrier in muscle. In ARF and SO mucles both AIB and cycloleucine uptake were indistinguishable in the absence or presence of insulin. Moreover, ARF caused no detectable abnormality in transport by systems ASC and L.

Acute Renal Failure - the Continuing Challenge

Acute potentially reversible renal failure (1, 2) can appear in patients in any branch of medicine, from the psychiatrically ill to women during and after pregnancy; thus it is a condition no doctorabove all no physician can ignore. The grim fact is that even in 1986, once oliguria resistant to cardiac support and volume replacement has set in, the patient has at best only an even chance of surviving. Why is it that despite great advances in almost all forms of treatment which might have improved survival, and the ability to substitute for absent renal function almost indefinitely, the mortality remains so distressingly high? One obvious answer is that acute renal failure is almost always secondary to some other event, and that the nature and severity of these events is so overwhelming that treatment has little effect. Today some of the 'milder' forms of acute renal failure, such as that following septic abortions of mismatched blood transfusions, have almost disappeared from clinical practice in developed countries, and we are left with a residuum of patients whose acute renal failure arises from a variety of circumstances, many of which carry in themselves a poor prognosis. At this point it should be made clear that here we are discussing only the variety of acute uraemia appearing in individuals with previously normal renal function, characterised in many patients by acute tubular necrosis, and normally running a course of several days to a few weeks, oliguria (<500 ml/24 h) (3); and that other causes of acute uraemia with oliguria, such as obstruction or acute glomerulonephritis, are not under consideration even though their early diagnosis by ultrasound or renal biopsy from the group considered here may be a crucial part of the early management of the syndrome of acute uraemia.

Lung fluid balance during acute renal failure in sheep.

To determine whether uremia changes lung vascular permeability, we measured the flow of lymph and proteins from the lungs of acutely uremic sheep. Acute renal failure was induced by either bilateral nephrectomy or by reinfusing urine. Both models of renal failure increased the plasma creatinine from 0.8 +/- 0.3 to 11 +/- 1 mg/dl in 3 days but caused no significant change in the flow of lymph from the lungs. To determine whether uremia increased the protein clearance response to elevated pulmonary microvascular pressures, we inflated a balloon in the left atrium for 2 h before and 3 days after inducing acute renal failure. In seven sheep, before removing the kidneys, the 20 cmH2O elevation of left atrial pressure increased the protein clearance 3.9 +/- 3.0 ml/h (from 9.5 +/- 4.9 to 13.4 +/- 5.4 ml/h). Three days after the bilateral nephrectomy the same increase in left atrial pressure increased the protein clearance 6.4 +/- 3.6 ml/h (from 6.1 +/- 2.1 to 12.5 +/- 5.2 ml/h), which was a significantly larger increase than that measured before the nephrectomy (P less than 0.05). Sham nephrectomy in seven sheep caused the protein clearance response to the elevated left atrial pressure to fall from 4.7 +/- 1.9 ml/h before the sham nephrectomy to 2.6 +/- 1.4 ml/h 3 days later (P less than 0.05). Uremia due to reinfusion of urine in five sheep did not affect the protein clearance response to elevations in left atrial pressure. Neither model of acute uremia increased the postmortem extravascular lung water volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurologic Complications of Renal Failure

T HE ASSOCIATION between abnormal renal function and central nervous system disease was recognized nearly 40 years ago . Seizures and coma were frequent complications of acute uremia , whereas peripheral neuropathy and encephalopathy, observed in progressive uremia, were terminal events. Despite improvements in the medical management of end-stage renal failure, including dialysis and transplantation, patients manifest a variety of neurologic disorders . The acute cerebral changes associated with uremia may present as the dialysis disequilibrium syndrome or as subdural, intracerebral or intraspinal hemorrhage; these bleeding diatheses occur in up to 10% of hypertensive hemodialysis patients . Potential toxins accumulating in uremia are numerous (see article by Powell et aI, this issue). To be considered a uremic toxin , the concentration of any putative compound should correlate better with some measurement of nerve or cerebral function than with a reduction in glomerular filtration rate. To date , this has not been convincingly demonstrated. The neurologic complications of arterial hypertension in children include convulsions in over 90 % of children with severe hypertension and facial palsy, blindness, paraplegia, and alterations in the level of consciousness.' Children may present with seizures as the first sign of hypertension. The prognosis for children having had a single episode of hypertensive encephalopathy is good, with no demonstrative neurologic deficit or focal abnormality on brain scan by computerized tomography.'

Specific defects in insulin-mediated muscle metabolism in acute uremia

The mechanisms underlying the abnormal insulin-mediated muscle glucose metabolism occurring in acute uremia (ARF) have not been identified. To characterize the defects, insulin dose-response curves for glucose uptake, glycogen synthesis, glucose oxidation, glycolysis, and lactate release were measured in incubated rat epitrochlearis muscles. ARF did not affect insulin sensitivity, but decreased the responsiveness to insulin of glucose uptake, glycogen synthesis, and glucose oxidation. Glycogen synthesis was subnormal at all levels of insulin and at the maximal insulin concentration; it was 54% lower in muscles of ARF compared to control rats. This inhibition of glycogen synthesis in ARF could be caused by a 23% decrease in the total activity of muscle glycogen synthase and the percentage of enzyme in the activated form. Glycogen phosphorylase activity was unchanged by ARF. ARF also increased the ratio of muscle lactate release to glucose uptake at concentrations of insulin from 10 to 10(4) microU/ml. In the absence and presence of insulin, muscle protein degradation was increased by ARF. In individual muscles incubated with insulin, the rate of proteolysis was correlated with the ratio of lactate release to glucose uptake (r = + 0.82; P less than 0.01). From the insulin dose-response relationships and changes in enzyme activities, we conclude that ARF increases protein degradation in muscle and causes abnormal insulin-mediated glucose metabolism. The abnormalities in glucose metabolism are caused by changes in post-receptor events.

Prolactin metabolic clearance and resistance to dopaminergic suppression in acute uremia.

A nephrectomized rat model was developed to examine PRL resistance to dopaminergic suppression, which is frequently present in humans with renal insufficiency. The MCR and the response of PRL to a dopamine (DA) infusion (0.4 microgram/kg . min) were measured in 24-h totally nephrectomized (TN) and sham-nephrectomized (SN) rats concurrently treated with alpha-methyl-p-tyrosine (AMPT), an inhibitor of DA synthesis. TN rats became significantly hyperprolactinemic within 1 day [36.2 +/- 7.1 vs. 18.5 +/- 2.5 (+/- SE) ng/ml; P less than 0.05]. SN and TN rats responded to AMPT with significant and sustained 3- and 5.5-fold increases in PRL, which DA reduced by 85% and 24%, respectively. Total nephrectomy decreased the PRL MCR by 58% (TN, 0.51 +/- 0.03; SN, 1.22 +/- 0.13 ml/min; P less than 0.001) and significantly increased the PRL secretion rate (TN, 79 +/- 10; SN, 37 +/- 8 ng/min; P less than 0.01). In the absence of DA infusion, AMPT reduced plasma DA to undetectable levels, while the median eminence DA contents in TN and SN rats were reduced to similar levels. Our data suggest that the totally nephrectomized rat is a suitable model to study PRL resistance to dopaminergic suppression, and that because DA does not cross the blood-brain barrier, the defect in uremia probably occurs at the level of the lactotroph.

Impaired muscle glucose metabolism in acute renal failure.

Renal failure is associated with peripheral insulin resistance and consequent carbohydrate intolerance. This report investigates carbohydrate metabolism in vitro in epitrochlearis and hemidiaphragm muscles taken from acutely uraemic and sham-operated rats. Muscles from acutely uraemic rats (compared to those from sham-operated rats) incubated with 5 mM glucose showed increased rates of basal and insulin-stimulated glycolysis and glycogen turnover, but pyruvate dehydrogenase and tricarboxylic acid-cycle flux was not increased in uraemia. Glycolysis (but not glycogen turnover) in muscles from acutely uraemic rats tended to show decreased responsiveness to stimulation by insulin. It is concluded that acute uraemia is associated with a defect(s) in muscle that produces intrinsic insulin resistance and results in diversion of glucose (both in basal and insulin-stimulated states) from glycogen synthesis into glycolysis.

Ultrastructure of the epithelial cells of the small intestinal villi, the surface epithelium of the large intestinal mucosa and some elements of the intestinal mucosal lamina propria in rats with acute uraemia

Electron microscopic studies on the dynamics of changes in the epithelial cells and some elements of the intestinal mucosal lamina propria were performed on rats after bilateral high ureter ligation. Simultaneously, they were referred to blood serum biochemical and electrolyte disturbances. The ultrastructural changes indicate that as early as in the initial period of acute uraemia water-electrolyte disturbances become evident, which are still increasing. In the later period cell organelles alter and bacterial infection sets in. Ultrastructural abnormalities of the intestinal mucous membrane are increasing proportionally to biochemical and electrolyte disturbances of the blood serum.

Excitability changes reveal decreased sodium permeability in neuropathy

Nerve excitability was tested in isolated sciatic nerves of rats with acute uremia. Larger than normal stimulating pulses were required to elicit a maximal compound potential, whereas the relative refractory period was unaffected. The threshold range, relative to the absolute threshold, was a good measure of the decreased excitability and may be a useful clinical method.

Experimental uremic neuropathy: Part 1. Decreased nerve conduction velocity in rats

Acute and chronic renal failure were induced in adult male albino rats by conventional surgical methods. The glomerular filtration rate of rats with chronic uremia was reduced to approximately 15% of normal. Despite this drastic degree of renal failure, the motor nerve conduction velocity (MCV) increased from 47.5 ± 6.4 m/s, preoperatively, to 55.6 ± 4.0 m/s after 4 weeks. In rats with acute uremia, MCV decreased from 51.4 ± 3.0 m/s to 45.2 ± 2.7 m/s after 48 h. The conduction velocity, measured in vitro of excised sciatic nerves was 55.2 ± 4.4 m/s in acute uremia and 64.7 ± 4.7 m/s in a control group. There was no difference in the refractory period between these groups. It is concluded that this decrease in the nerve conduction velocity was not caused by changes in the composition of the extracellular fluid but rather by changes in the nodal membrane function.

Experimental uremic neuropathy: Part 2. Sodium permeability decrease and inactivation in potential clamped nerve fibers

Potential recordings and potential clamp of isolated myelinated fibers from the sciatic nerve of acutely uremic rats showed a marked decrease in excitability related to a decrease in the specific Na permeability (P Na) of the nodal membrane. Mean value of the available P Na in the resting node of the uremic rats was 24% of the P Na in a control group. This change explained the decreased nerve conduction velocity in the acutely uremic rat. The Na current reversal potential was decreased in some fibers, reflecting an axoplasmic Na accumulation. The decrease in P Na was to a large extent caused by an increased inactivation, due to a negative shift (about 10 mV) of the steady state inactivation curve along the potential axis. The activation of P Na was similarly shifted (about 10 mV) to a more negative potential region. Such changes may be caused by elevated intracellular [Ca], suggesting a disturbance in Ca metabolism or an intracellular accumulation of cationic metabolites (which possibly have a similar effect) in rats with acute uremia.

Role of uremia, brain calcium, and parathyroid hormone on changes in electroencephalogram in chronic renal failure.

Acute uremia is associated with increased calcium (Ca) in brain and changes in electroencephalogram (EEG), and both derangements are related to excess parathyroid hormone (PTH). Also changes in EEG in patients with chronic renal failure (CRF) correlated directly with blood levels of PTH, and fall in PTH was followed by improvement in EEG. We examined whether chronic uremia per se has an effect on brain calcium or EEG. Uremia was produced by 5/6 nephrectomy and maintained for 32-70 wk in seven thyroparathyroidectomized (TPTX) and seven control dogs. There were no differences in creatinine clearance and serum electrolytes except for HCO3, which was lower in control animals (P less than 0.01). Serum PTH was undetectable in TPTX dogs but was significantly elevated in control animals (32.3 +/- 3.3 mu leq /ml). Calcium in gray and white matter was significantly increased in both groups but much higher in control animals. The percent waves of less than 7 Hz in EEG were similar in both groups prior to uremia (TPTX 4.6 +/- 0.8 vs. control 4.2 +/- 0.5%) but remained unchanged in TPTX animals and increased significantly in control dogs (19.0 +/- 1.3%) after uremia. These data suggest that CRF per se is associated with marked rise in Ca in both gray and white matter and increment is higher in the presence of PTH. Disturbance in EEG in a state of CRF requires the presence of excess PTH and is prevented despite increased Ca in brain if hyperparathyroidism is not allowed to develop.

Prolactin plasma levels and its size heterogeneity in acutely uremic rats.

The size distribution pattern of circulating rPRL was studied in intact control (C) rats and in three uremic models, namely urine autoinfusion (UA), bilateral ureteral ligation (BUL), and bilateral nephrectomy (BNx). Plasmas were chromatographed by gel filtration in Sephadex G-100. Rat PRL was measured by RIA. The rPRL levels as well as the size distribution pattern of UA were similar to that of C. BUL and BNx showed a similar degree of hyperprolactinemia which corresponded to an increase in little rPRL. The results suggest that acute uremic hyperprolactinemia seems to be the result of accumulation of little rPRL. Acute uremia by itself does not increase rPRL plasma levels nor does it seem to affect the size distribution pattern of circulating rPRL.

Stimulation of cardiac contractility by catecholamines is diminished in experimental uremia.

Cardiovascular complications are common among uremic patients. Various factors such as hypertension, anemia, acidosis, overhydration and hyperkalemia may interfere with cardiac function and explain the high cardiovascular mortality of uremic patients. Therefore, much controversy exists as to whether these factors explain the cardiac dysfunction or whether some specific “uremic cardiomyopathy” exists (1, 2). To further clarify this issue, a model of acute uremia, in which all the above factors were absent, was chosen to study myocardial performance in uremia.KeywordsCardiac ContractilityLeft Ventricular PressureUremic PatientLactate PyruvateChronic UremiaThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.