Biomedical subjects
M Walser
Publications and source records attributed to M Walser.
Utilization of alpha-ketoisocaproate for synthesis of hepatic export proteins and peripheral proteins in normal and cirrhotic subjects.
The ratio R, defined as (percent of dose of 14C)/(percent of dose of 3H) in the leucine of plasma fibrinogen, albumin, immunoglobulin G (IgG), red cell globin, and salivary mucin, was measured in 7 normal adults and in 5 cirrhotic patients during continuous intragastric infusion of 1-14C-labeled alpha-ketoisocaproate (KIC) and 3H-labeled leucine. The ratio R measured in whole body protein has been shown in rat experiments to be a measure of the nutritional efficiency of KIC relative to leucine. In normal subjects, R in albumin and fibrinogen became constant (0.63 +/- 0.05) after the third hour and were indistinguishable from one another. The ratio R in IgG was similar and constant. The ratio R in plasma leucine (0.62 +/- 0.06) was significantly lower than R in mucin (0.86 +/- 0.04) or globin (0.73 +/- 0.04), indicating that these latter proteins derive a significant fraction of their leucine from KIC transaminated locally, rather than from circulating leucine. Results in 5 cirrhotic patients were the same, except that R in IgG and R in globin were significantly increased. Thus, cirrhosis does not alter the efficiency, relative to leucine, with which oral KIC is used for synthesis of export proteins by the liver, but increases the efficiency with which it is used for the synthesis of some proteins peripherally.
Utilization of alpha-ketoisocaproate for protein synthesis in uremic rats.
We have recently shown that the nutritional efficiency, R, of alpha-ketoisocaproate (KIC) as a substitute for leucine, defined as the ratio of the dose of leucine to the dose of KIC (on a leucine-free diet) for equal growth, can be evaluated isotopically: 14C-KIC and 3H-leucine are administered p.o.; six hours later, 14C/3H in the leucine of whole body protein, divided by 14C/3H in the injectate, gives a value distinguishable from R assessed in the same animals by growth experiments. To see how chronic uremia affects R, 11/12 nephrectomized rats and sham-operated controls were fed a regular diet for 15 days and then given these isotopes p.o. Six hours later, R, measured in whole body protein, and in the protein of brain, heart, muscle, salivary gland, liver, and the kidney remnant was significantly greater than in sham-operated controls. The greatest difference (39%) was seen in liver protein and the smallest difference (19%) in muscle. Thus chronic uremia increases the efficiency, relative to leucine, with which KIC is utilized for protein synthesis in all of these organs and in the body as a whole. Possible explanations are discussed.
Effect of the level of dietary protein on the utilization of alpha-ketoisocaproate for protein synthesis.
The efficiency of alpha-ketoisocaproate (KIC) as a dietary substitute for leucine in rats on varying protein intake was estimated by an isotopic method, previously shown to yield the same results as comparative growth experiments. 14C-KIC and 3H-leucine are injected orally. Six hours later the ratio, R, of 14C/3H in isolated proteins, divided by the same ratio in the injectate is measured. This ratio has been shown to be approximately equal to nutritional efficiency of KIC relative to leucine. As dietary protein increased from 6.3% to 48.3%, whole body protein R decreased from 0.515 +/- 0.045 to 0.299 +/- 0.016. Variations with protein intake were noted in R of protein isolated from individual organs. The magnitude of R in these organs varied two-fold, in the following sequence: brain greater than heart greater than or equal to skeletal muscle greater than or equal to salivary gland greater than or equal to kidney greater than liver. Whole body protein R could be confidently predicted (r2 = 0.992) from R in the protein of kidney and muscle. Thus the nutritional efficiency of KIC as a dietary substitute for leucine in individual organs as well as in the whole animal is strongly dependent on the level of protein intake.
Phenomenological analysis of renal regulation of sodium and potassium balance.
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Nutritional efficiency of alpha-ketoisocaproate relative to leucine, assessed isotopically.
The efficiency of alpha-ketoisocaproate as a dietary substitute for leucine was assessed in rats by two techniques: first, the minimal dose of alpha-ketoisocaproate required, as a supplement to a leucine-free diet, to achieve a growth rate as great as animals receiving leucine was found to be between 2.2 and 4.4 times larger. Therefore the nutritional efficiency of alpha-ketoisocaproate lies between 0.23 and 0.46. Second, alpha-[1-14C]-ketoisocaproate and [3H]leucine were administered orally and the ratio of 14C/3H incorporated into the leucine of whole-body protein and fibrin was measured. This ratio, divided by the ratio 14C/3H injected, was the same in fibrin as in whole-body protein and averaged 0.39. Thus both techniques yield the same value, within the error of measurement, for the relative nutritional efficiency of alpha-ketoisocaproate. We also found that alpha-ketoisocaproate feeding at varying dosage did not alter this ratio in whole-body protein (measured in rats fasted overnight), suggesting that neither wide variations in growth rate nor exposure for 10 days to alpha-ketoisocaproate (in a diet of constant protein content) alters the relative rates of utilization (or oxidation) of alpha-ketoisocaproate vs. leucine.
The effect of a keto acid-amino acid supplement to a restricted diet on the progression of chronic renal failure.
We treated 24 patients who had chronic renal failure with a low-phosphorus diet containing 20 to 30 g of mixed-quality protein, supplemented by amino acids and their keto analogues. Seventeen patients had well-defined rates of progression before treatment, as assessed by serial determinations of serum creatinine levels. By extrapolating these rates of progression, we found that 10 of the 17 (59 per cent) had a clinically important slower rise in creatinine levels during long-term treatment (average, 20 months) than predicted; none had a faster rise than predicted. Seven of the 17 patients began treatment before creatinine reached the level of 8 mg per deciliter; in six of the seven, followed for an average of 22 months, creatinine has remained at or below the level at the start of treatment. Nutrition, as assessed by body weight, nitrogen balance, serum albumin, and serum transferrin, has been well maintained. This regimen slowed or arrested the rise in creatinine levels and thus must have slowed or halted the progression of renal insufficiency in a majority of cases, especially when treatment was initiated before creatinine had reached the level of 8 mg per deciliter. The mechanism underlying this effect remains to be determined.
Therapeutic aspects of branched-chain amino and keto acids.
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Effects of alpha-ketoisocaproate and of leucine on nitrogen metabolism in postoperative patients.
21 patients undergoing major abdominal surgery were randomly assigned to one of three groups. On the day of surgery and for the succeeding 4 days each group received a daily infusion of one of the following: 10 g glucose plus 70 mmol NaHCO3, 70 mmol leucine plus 70 mmol NaHCO3, or 70 mmol of sodium alpha-ketoisocaproate (KIC). No other calories were given. Leucine infusions had no significant effect on nitrogen (N) balance, 3-methylhistidine excretion, or plasma concentrations of pre-albumin or retinol-binding protein, but they increased blood acetoacetate concentration (p = 0.004). N balance was less negative (p = 0.002) and 3-methylhistidine excretion lower (p = 0.002) in the group receiving KIC than in those receiving glucose. Blood ketone bodies, plasma prealbumin, and plasma retinol-binding protein concentrations at the end of the study were significantly higher in the KIC group than in the others. These N-sparing effects of KIC may be related to the heightened ketosis that followed its administration, to suppression of protein degradation, or to an effect on liver protein turnover. KIC alone in small doses diminishes N wastage in postoperative but under the same conditions leucine does not.
Nutritional support in renal failure: future directions.
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Growth of rats with severe renal insufficiency fed a formula designed to minimize urinary solutes.
Experiments were designed to test the hypothesis that growth depression and azotemia in chronic renal failure can be minimized by providing a nutritional formula that is adequate is essential nutrients but minimizes urinary excretion of all solutes. Unrestrained rats were fed exclusively by continuous intragastric infusion with a mixture containing sucrose, essential amino acids, N-free analogues thereof, minerals, corn oil, and vitamins, designed to minimize urinary solute excretion while permitting growth. After 5 days, renal excretory function was reduced to 1/10 by reinfusing 90% of each day's urinary output intragastrically for the next 3 wk. Weight gain (3.6 +/- 0.1 g/day), linear growth and carcass N accretion were the same as in nonreinfused rats receiving substantially the same formula by intragastric catheter. Except for sight acidosis (CO2 18.5 mM) accumulation of electrolytes did not occur. Average final serum urea N was only 42.5 +/- 7.1 mg/dl. The results are considered as supporting the hypothesis.
Nutrition in renal failure.
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Aldosterone response in the turtle bladder is associated with an increase in ATP.
Urinary bladders from freshwater turtles, mounted as sacs, were stripped of their serosa and submucosa. This did not alter conductance. They were maintained in open circuit except for brief observation of short-circuit current (SCC) every 15 min. Potential difference (PD) averaged 68 +/- 14 mV and SCC 485 +/- 100 microA. Acetazolamide 10(-3) M increased SCC by 46 +/- 27 microA. Aldosterone 10(-7) M following acetazolamide resulted in a rise in SCC that began at about 75 min and reached a plateau between 3 and 5 h. SCC rose 127 +/- 15% compared with control bladder halves. ATP measured in perchloric acid extracts 5 h after addition of aldosterone increased by 33% (P less than 0.01) and (ATP)/(ADP) X (Pi) by 81% (P less than 0.01). These results support the view that the stimulatory effects of aldosterone on active sodium transport involve an increase in ATP and (ATP)/(ADP) X (Pi).
Supplements containing amino acids and keto acids in the treatment of chronic uremia.
Three mixtures containing varying proportions of threonine, tyrosine, and the ornithine, lysine, and histidine salts of branched-chain keto acids have been tested as dietary supplements to a 20- to 25-g mixed-quality protein diet in patients with severe chronic uremia. Two of the three supplements improved the abnormalities of plasma amino acid concentrations, and slowed or arrested progression of renal insufficiency. The second supplement, which contained less threonine and lysine, led to subnormal plasma concentrations of these two amino acids and aggravated hypophosphatemia. The third supplement, which also contained a small amount of the hydroxy analogue of methionine, was the most effective in slowing progression. The results emphasize the importance of optimizing the composition of such supplements.
Branched-chain ketoacids reduce muscle protein degradation in Duchenne muscular dystrophy.
In order to determine whether branched-chain ketoacids can reduce the excessive rate of muscle protein degradation that characterizes Duchenne muscular dystrophy, nine boys affected with the disease were studied in a metabolic ward while receiving meat-free diets. After a three-day equilibration period, excretion rates of 3-methylhistidine and creatinine were measured in two consecutive four-day periods. In the second period, a supplement containing a mixture of ornithine alpha-ketoisocaproate, alpha-ketoisovalerate, and alpha-keto-beta-methylvalerate in a proportion of 4:1:1 was administered orally at a dosage of 0.45 gm/kg/day. During treatment with the ketoacids, 3-methylhistidine excretion fell by a small (mean: 14%) but highly significant (P less than 0.01) extent, whether expressed in absolute terms or in relation to creatinine excretion. No adverse effects were noted. We conclude that this mixture of ketoacids acutely reduces muscle protein degradation in patients with Duchenne muscular dystrophy.
Nutritional management of chronic renal failure.
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Long-term effects of a new ketoacid-amino acid supplement in patients with chronic renal failure.
Nine patients with severe chronic renal failure (mean glomerular filtration rate 4.8 ml/min; mean serum creatinine 11.3 mg/dl) who were previously on a protein-restricted diet were treated with a diet containing an average of 33 kcal/kg and 22.5 g/day of mixed quality protein, supplemented by a combination of amino acids and mixed salts formed between basic amino acids and keto-analogues of essential amino acids. The supplement was designed to minimize or reverse the amino acid abnormalities of chronic renal failure rather than to meet the normal requirements for the essential amino acids; it contained tyrosine, ornithine, and a high proportion of branched-chain ketoacids, but no phenylalanine or tryptophan and very little methionine. Within one month, serum urea nitrogen fell and serum albumin and transferrin rose significantly; serum creatinine fell slightly. Hyperphosphatemia (present in three patients) was corrected. Nitrogen balance, measured in seven of the nine patients, on the average was neutral, as it was in a preceding control period on a 40 to 50 g/day protein diet. Plasma tyrosine and threonine, which were subnormal before therapy, rose to normal or high normal levels. Branched-chain amino acids did not change. During a total of 63 patient-months of therapy, no side effects or toxicity were observed, and serum albumin and transferrin did not change further. It is concluded that this specially designed supplement added to a 20 to 25 g/d protein diet is an acceptable regimen which can improve or maintain protein nutrition in patients with severe chronic renal failure who would otherwise require dialysis.
Nitrogen utilization in uremic patients fed by continuous nasogastric infusion.
Patients with severe renal failure were continuously fed an electrolyte-free solution containing oligosaccharides plus 35 g of a mixture of six amino acids and four (or, in one study, five) nitrogen-free analogues via a small-bore nasogastric tube attached to a pump. They also ingested three small meals daily. Total caloric intake averaged 34 kcal/kg (of which 76% was infused). Total nitrogen intake averaged only 3.3 g (of which 68% was infused). Nevertheless, nitrogen balance was positive (average + 1.22 g/day). All components of nitrogen excretion fell to unusually low average values: urea nitrogen appearance, 1.14 g/day; non-urea urinary nitrogen. 0.63 g/day; fecal nitrogen, 0.48 g/day. Nitrogen requirement for balance on this regimen, estimated from linear regression, was only 2.0 g/day. Body weight did not change significantly. Serum albumin and transferrin remained normal. Thus, this regimen induces positive nitrogen balance despite low nitrogen intake.