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Biomedical subjects

W E Mitch

Publications and source records attributed to W E Mitch.

At least 37 records · Page 2Linked to original sources
PubMed2000

The losartan renal protection study--rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan).

The RENAAL Study is a double-blind, placebo-controlled trial to evaluate the renal protective effects of losartan in Type 2 diabetic patients with nephropathy. The study has enrolled 1513 patients and is expected to continue for 3.5 years after the last patient has been entered. Eligible patients must have a urinary albumin:creatinine ratio of at least 300 mg/g and serum creatinine between 1.3 to 3.0 mg/dL. Eligible hypertensive or normotensive patients are randomised to receive either losartan or placebo, in addition to their existing antihypertensive therapy. Medications that block angiotensin production or action, are excluded. The primary endpoint is a composite of the time to first event of doubling of serum creatinine, end-stage renal disease, or death; secondary endpoints include cardiovascular events, progression of renal disease, and changes in proteinuria; tertiary endpoints include quality of life, healthcare resource utilisation, and amputations. Patients include Caucasians (48.6%), Blacks (15.2%), Asians (16.7%), and Hispanics (18.2%). Baseline urinary albumin:creatinine ratio and serum creatinine levels average 1867 mg/g and 1.9 mg/dL, respectively. Mean systolic and diastolic blood pressures are 153 and 82 mmHg, respectively. RENAAL will document whether blockade of the AII receptor with losartan produces clinical benefits in patients with Type 2 diabetes and nephropathy.

Aged↗
PubMed2000

Dietary therapy in uremia: the impact on nutrition and progressive renal failure.

BACKGROUND: In rats with experimental chronic renal failure (CRF), low-protein diets protect against histologic damage and improve mortality. In CRF patients, low-protein diets ameliorate uremic symptoms and certain CRF complications. Fortunately, low-protein diets are nutritionally sound in CRF patients because they activate compensatory mechanisms that conserve protein with a low-protein diet. These results do not determine if dietary protein restriction can slow the rate of progression of CRF or the time to dialysis. METHODS: Reports evaluating low-protein diets and changes in nutritional status and/or progression of CRF are analyzed for efficacy. The MDRD Study is reviewed in depth. RESULTS: When dietary compliance was achieved, the nutritional status was unimpaired and progression was slowed. Studies with limited dietary compliance failed to find any beneficial effect on progression. Problems in study design suggest caution before accepting the initial MDRD Study conclusion that dietary restriction does not slow progression. Subsequent analyses of MDRD results indicate that protein restriction can slow progression of CRF. CONCLUSION: Evidence that dietary protein spontaneously decreases in progressively uremic patients should not be construed as an argument against the use of dietary therapy. Rather, it is a persuasive argument to restrict dietary protein intake in order to minimize CRF complications while preserving nutritional status. In patients with uremia or progression despite other measures, dietary therapy should be started along with monitoring for dietary compliance and nutritional adequacy.

Diet, Protein-Restricted↗
PubMed2000

Mechanisms accelerating muscle atrophy in catabolic diseases.

In summary, muscle protein loss in uremia is related to activation of the ubiquitin-proteasome proteolytic system to degrade muscle proteins. This response invariably includes increased transcription of genes encoding components of this pathway, suggesting that these illnesses stimulate a program of catabolism. Signals that could activate muscle protein degradation by this system in CRF include metabolic acidosis, impaired response to insulin and high circulating levels of cytokines. The activation mechanism also involves glucocorticoids which are necessary but not sufficient to activate protein degradation in muscle.

Adenosine Triphosphate↗
PubMed1999

Changing glomerular filtration with progression from impaired glucose tolerance to Type II diabetes mellitus.

Glomerular filtration rate (iothalamate clearance) was measured serially for 48 months in 26 Pima Indians with impaired glucose tolerance and 27 with normal glucose tolerance. At baseline, the mean glomerular filtration rate (SEM) was 133+/-8 ml/min in subjects with impaired glucose tolerance and 123+/-5 ml/min in those with normal glucose tolerance (p = 0.12). In the 12 subjects with impaired glucose tolerance who progressed to Type II (non-insulin-dependent) diabetes during follow-up, mean glomerular filtration rate increased by 30% (p = 0.011). Among the remaining 14 subjects with impaired glucose tolerance, 12 reverted to normoglycaemia. The glomerular filtration rate both at baseline and after 48 months in this subgroup exceeded the values of subjects with normal glucose tolerance by 20 % (p = 0.008) and 14% (p=0.013), respectively. A pronounced rise in the glomerular filtration rate occurs at the onset of Type II diabetes but a trend to hyperfiltration is also present in those with impaired glucose tolerance.

Analysis of Variance↗
PubMed1999

Factors causing malnutrition in patients with chronic uremia.

There is abundant evidence that patients with chronic renal failure (CRF), including those treated by hemodialysis or peritoneal dialysis, have evidence of malnutrition with decreased body weight and subnormal values of serum proteins (suggesting a loss of visceral protein stores). Potential causes of an abnormal nutritional status that have been identified include an inadequate intake of protein or calories, an inability to activate the metabolic responses that are needed to achieve nitrogen and protein balance, or the presence of a disease that prevents activation of these metabolic responses or acts to stimulate the breakdown of body protein stores. Three critical metabolic responses to a limited protein intake have been identified: a reduction in the irreversible degradation of amino acids and the degradation of protein breakdown and an increase in protein synthesis in response to a meal. Metabolic acidosis blocks the first two responses and hence contributes to malnutrition in patients with chronic uremia. Other factors that could contribute to malnutrition include an inadequate intake because of anorexia or hormonal imbalances that impair protein turnover. In evaluating CRF patients with malnutrition, the first task is to ensure an adequate intake and to eliminate factors that impair the ability to achieve nitrogen balance.

Chronic Disease↗
PubMed1999

Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting.

The ubiquitin-proteasome proteolytic system is stimulated in conditions causing muscle atrophy. Signals initiating this response in these conditions are unknown, although glucocorticoids are required but insufficient to stimulate muscle proteolysis in starvation, acidosis, and sepsis. To identify signals that activate this system, we studied acutely diabetic rats that had metabolic acidosis and increased corticosterone production. Protein degradation was increased 52% (P < 0.05), and mRNA levels encoding ubiquitin-proteasome system components, including the ubiquitin-conjugating enzyme E214k, were higher (transcription of the ubiquitin and proteasome subunit C3 genes in muscle was increased by nuclear run-off assay). In diabetic rats, prevention of acidemia by oral NaHCO3 did not eliminate muscle proteolysis. Adrenalectomy blocked accelerated proteolysis and the rise in pathway mRNAs; both responses were restored by administration of a physiological dose of glucocorticoids to adrenalectomized, diabetic rats. Finally, treating diabetic rats with insulin for >/=24 h reversed muscle proteolysis and returned pathway mRNAs to control levels. Thus acidification is not necessary for these responses, but glucocorticoids and a low insulin level in tandem activate the ubiquitin-proteasome proteolytic system.

Acidosis↗
PubMed1999

Angiotensin II stimulates gene expression of cardiac insulin-like growth factor I and its receptor through effects on blood pressure and food intake.

Angiotensin II (Ang II) is known to act as a growth factor and may be involved in cardiac remodeling. We have shown that insulin-like growth factor-I (IGF-I) is an autocrine mediator of growth responses to Ang II in vascular smooth muscle cells in vitro, and we hypothesized that IGF-I also serves as an important modulator of cardiovascular growth in vivo. To study the effect of Ang II on cardiac IGF-I, we infused rats for 3, 7, or 14 days with Ang II through osmotic minipumps. After 7 days, left ventricular mass normalized for body weight was increased by 20% (P<0.01) in Ang II rats compared with pair-fed control rats that were given a restricted amount of food identical to that eaten by the anorexic, Ang II-infused rats. Ang II increased left ventricular IGF-I mRNA levels by 1.5- to 1.8-fold compared with ad libitum-fed or pair-fed control rats (P<0.05). Cardiac IGF-I protein was increased correspondingly and was localized on the cardiomyocytes. Treatment with hydralazine abolished the induction of IGF-I mRNA, which indicates that Ang II induces cardiac IGF-I mRNA expression through a pressor-mediated mechanism. IGF-I receptor (IGF-IR) mRNA was induced 2.1-fold in Ang II rats compared with ad libitum-fed rats (P<0.01). However, this increase was also observed in pair-fed controls and is thus due to the anorexigenic effect of Ang II. We have recently shown that circulating IGF-I levels are reduced in response to Ang II infusion. Elevation of IGF-I levels by coinfusion of IGF-I and Ang II significantly increased left ventricular index by 16% compared with rats infused with Ang II alone (P<0.05). In conclusion, autocrine upregulation of cardiac IGF-I and IGF-IR mRNA by Ang II occurs through hemodynamic and nonhemodynamic mechanisms, respectively, and may modulate cardiac structural changes that occur in hypertension.

Angiotensin II↗
PubMed1999

Ubiquitin conjugation by the N-end rule pathway and mRNAs for its components increase in muscles of diabetic rats.

Insulin deficiency (e.g., in acute diabetes or fasting) is associated with enhanced protein breakdown in skeletal muscle leading to muscle wasting. Because recent studies have suggested that this increased proteolysis is due to activation of the ubiquitin-proteasome (Ub-proteasome) pathway, we investigated whether diabetes is associated with an increased rate of Ub conjugation to muscle protein. Muscle extracts from streptozotocin-induced insulin-deficient rats contained greater amounts of Ub-conjugated proteins than extracts from control animals and also 40-50% greater rates of conjugation of (125)I-Ub to endogenous muscle proteins. This enhanced Ub-conjugation occurred mainly through the N-end rule pathway that involves E2(14k) and E3alpha. A specific substrate of this pathway, alpha-lactalbumin, was ubiquitinated faster in the diabetic extracts, and a dominant negative form of E2(14k) inhibited this increase in ubiquitination rates. Both E2(14k) and E3alpha were shown to be rate-limiting for Ub conjugation because adding small amounts of either to extracts stimulated Ub conjugation. Furthermore, mRNA for E2(14k) and E3alpha (but not E1) were elevated 2-fold in muscles from diabetic rats, although no significant increase in E2(14k) and E3alpha content could be detected by immunoblot or activity assays. The simplest interpretation of these results is that small increases in both E2(14k) and E3alpha in muscles of insulin-deficient animals together accelerate Ub conjugation and protein degradation by the N-end rule pathway, the same pathway activated in cancer cachexia, sepsis, and hyperthyroidism.

Animals↗
PubMed1999

Nutrition and chronic renal failure in rats: what is an optimal dietary protein?

In chronic uremia (CRF), malnutrition is an important determinant of morbidity in adults and impaired growth in children. Causes of malnutrition include anorexia and abnormal protein and amino acid metabolism. To determine how different levels of dietary protein and CRF interact to influence growth and nutritional status, CRF and sham-operated, pair-fed control rats were fed isocaloric diets containing 8, 17, or 30% protein for 21 d to mimic dietary regimens recommended for CRF patients: the minimum daily requirement; the recommended daily allowance; or an excess of dietary protein. Serum creatinine did not differ between groups of CRF rats but blood urea nitrogen was lowest in CRF rats fed 8% protein (P < 0.001). CRF rats eating 30% protein gained less weight and length compared to their controls or CRF rats fed 8 or 17% protein (P < 0.05); they also had acidemia. CRF rats fed 8% protein had the highest efficiency of utilization of protein for growth, while 17% protein promoted the highest efficiency of utilization of food and calories for growth. Notably, CRF rats eating 30% protein had the lowest protein efficiency; their calorie intake was also the lowest because of anorexia. Plasma branched-chain amino acids were progressively higher in control rats eating 8, 17, or 30% protein. CRF rats fed 8 or 17% protein had lower branched-chain amino acid concentrations compared with CRF rats fed 30% protein. In CRF, it is concluded that excessive dietary protein impairs growth but a low-protein diet does not impair nutritional responses and permits utilization of protein for growth if calories are sufficient.

Amino Acids, Branched-Chain↗
PubMed1998

Nutritional considerations and the indications for dialysis.

Evidence of a reduction in dietary protein intake and some indices of nutritional status in chronic renal failure (CRF) patients consuming unrestricted diets has led some individuals to recommend that low-protein diets be avoided and that dialysis should be initiated if the protein intake declines below 0.8 g protein/kg/day. However, evidence indicates that when properly implemented, low-protein diets are safe and can maintain lean body mass even during long-term therapy. This is because CRF patients are able to activate normal compensatory responses when protein intake is restricted, and their protein and energy requirements are similar to healthy subjects. Because low-protein diets ameliorate uremic symptoms and some of its metabolic complications, dietary therapy should be attempted in all patients with progressive CRF. The recommendation to initiate dialysis when the protein intake declines below 0.8 g/kg/day should be viewed with skepticism because mortality risk is increased in end-stage renal disease (ESRD) patients and dialysis therapy does not improve protein and energy intake or ameliorate malnutrition.

Diet, Protein-Restricted↗
PubMed1998

Robert H Herman Memorial Award in Clinical Nutrition Lecture, 1997. Mechanisms causing loss of lean body mass in kidney disease.

Loss of lean body mass is common in patients with acute or chronic renal failure but the mechanisms causing this loss are only beginning to be understood. One mechanism involves an inability of uremic patients to activate the critical metabolic responses that maintain protein balance when dietary protein is limited. Metabolic responses to dietary protein restriction include a sharp reduction in the degradation of essential amino acids and protein; changes in protein synthesis are less reliable. If uremia prevents suppression of essential amino acid or protein degradation when dietary protein is reduced by anorexia, negative nitrogen balance and loss of lean body mass will ensue. One complication of uremia, metabolic acidosis, stimulates the degradation of branched-chain amino acids and proteins and therefore blocks the ability of the patient to respond to a low-protein diet. The mechanisms require glucocorticoids and involve increased activity of branched-chain keto acid dehydrogenase and the ubiquitin-proteasome proteolytic pathway; there also is increased transcription of genes encoding components of enzymes involved in the pathways. Besides acidosis, a low insulin concentration and cytokines activate the ubiquitin-proteasome proteolytic pathway. Understanding how proteolysis is activated, including how these genes are stimulated, is important because the same pathways are activated in diabetes, cancer, sepsis, burns, starvation, and muscle denervation. Activation of the ubiquitin-proteasome pathway leads to reduced lean body mass.

Cachexia↗
PubMed1998

Mechanisms stimulating protein degradation to cause muscle atrophy.

Catabolic conditions such as uremia, cancer, insulin-dependent diabetes and sepsis are associated with muscle atrophy resulting from activation of the ubiquitin-proteasome proteolytic pathway. Evidence for the activation of this pathway includes an increase in both proteolytic activity and capacity, as demonstrated by increased protein degradation and a higher rate of gene transcription in muscle yielding increased levels of mRNAs encoding components of the pathway. Glucocorticoids are critical but other hormones and cytokines interact to regulate the activity of this proteolytic pathway.

Animals↗
PubMed1998

Nutritional considerations in the treatment of patients with chronic uremia.

Low-protein diets ameliorate uremic symptoms and some of its metabolic complications. These diets can be used successfully to treat patients with chronic renal failure (CRF) because they are able to activate normal compensatory responses when protein intake is restricted and their protein and energy requirements are similar to healthy subjects. However, there has been concern that dietary therapy compromises the nutritional status of CRF patients and that initiating dialysis would be preferable to this type of therapy. Kopple and co-workers have identified the requirements of CRF patients for protein and calories and available evidence indicates that when properly implemented, low-protein diets are safe and can maintain lean body mass even during long-term therapy. Based on the information published by Kopple and co-workers, the strategies for treating CRF patients should include careful analysis of the diet and the nutritional status of the patient.

Diet, Protein-Restricted↗
PubMed1998

Mechanisms contributing to muscle-wasting in acute uremia: activation of amino acid catabolism.

Acute uremia (ARF) causes metabolic defects in glucose and protein metabolism that contribute to muscle wasting. To examine whether there are also defects in the metabolism of essential amino acids in ARF, we measured the activity of the rate-limiting enzyme for branched-chain amino acid catabolism, branched-chain ketoacid dehydrogenase (BCKAD), in rat muscles. Because chronic acidosis activates muscle BCKAD, we also evaluated the influence of acidosis by studying ARF rats given either NaCl (ARF-NaCl) or NaHCO3 (ARF-HCO3) to prevent acidosis, and sham-operated, control rats given NaHCO3. ARF-NaCl rats became progressively acidemic (serum [HCO3] = 21.3 +/- 0.7 mM within 18 h and 14.7 +/- 0.8 mM after 44 h; mean +/- SEM), but this was corrected with NaHCO3. Plasma valine was low in ARF-NaCl and ARF-HCO3 rats. Plasma isoleucine, but not leucine, was low in ARF-NaCl rats, and isoleucine tended to be lower in ARF-HCO3 rats. Basal BCKAD activity (a measure of active BCKAD in muscle) was increased more than 17-fold (P < 0.01) in ARF-NaCl rat muscles, and this response was partially suppressed by NaHCO3. Maximal BCKAD activity (an estimate of BCKAD content), subunit mRNA levels, and BCKAD protein content were not different in ARF and control rat muscles. Thus, ARF increases branched-chain amino acid catabolism by activating BCKAD by a mechanism that includes acidosis. Moreover, in a muscle-wasting condition such as ARF, there is a coordinated increase in protein and essential amino acid catabolism.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗