No abstract

Urea has long been considered to be metabolically inert. However, recent studies with isotopic urea in several species of animals have revealed that urea is hydrolyzed in the alimentary tract even when administered parenterally (1-5). This breakdown is presumably due to the action of bacterial urease, since urea metabolism can be eliminated or reduced to negligible proportions by the administration of antibiotics.In the studies reported herein, labeled urea was administered intravenously to normal subjects and the rate of extrarenal disposal was determined. Both N15-and C14-labeled materials were employed in order to minimize the problem of reincorporation of tracer atoms into urea. In the case of N'5, enriched ammonia produced by urea hydrolysis in the gut becomes reincorporated into newly formed urea. In the case of C14, recent evidence (6) suggests that reincorporation into urea of labeled CO2, formed by bacterial ureolysis in the gut, may also occur; a conclusion supported by the present experiments.Despite these limitations, the results indicate that 15 to 30 per cent of the urea being synthesized in normal subjects is continually being destroyed. This breakdown can be eliminated by oral administration of neomycin. METHODSUrea containing 60.9 atoms per cent N"5 was synthesized by the ammonolysis of diphenyl carbonate (7) and purified by recrystallization.' The resulting product had a melting point of 130°C. (uncorrected). The nitrogen content was 46.7 per cent (calculated 46.7 per cent).

Commercial inulin available at present is not a homogeneous product (1). It consists of two major fractions the proportions of which vary: (a) a portion of relatively large molecular weight resistant to heating in alkali; and (b) a portion of smaller molecular weight susceptible to destruction with alkali. In addition, most samples contain a small percentage of fructose, which also yields color in the analytical methods for inulin unless removed by treatment with yeast or hot alkali.Two recent reports (2, 3) indicate that the clearance of the alkali-stable and alkali-labile fractions of inulin may not be equal. Since some commercial preparations of inulin (such as the one used in this study) may contain as much as 50 per cent of the alkali-labile material, considerable errors in estimation of glomerular filtration rate would occur if a difference in clearance of the two fractions exists.The present report indicates that the clearance of the two fractions is identical, within the limits of error of analysis, in confirmation of the preliminary report by Cotlove (1). METHODSSubjects. The subjects were patients of the National Heart Institute at the Clinical Center. One was a normal volunteer. The others had renal or endocrine diseases. In most cases studies were performed in the fasting state. The comparisons were made during clearance determinations performed for other purposes.Procedure. Before each clearance determination, the ampoules of inulin to be used were mixed together and a portion withdrawn for analysis.' A priming injection and a sustaining infusion of inulin were administered intravenously. The plasma level of the alkali-stable fraction was approximately 13 mg. per cent. After a 30 to 40-minute equilibration period, 3 to 8 urine collection periods were obtained, each of 20 to 40 minutes' duration.

The use of the creatinine height index (CHI) as a measure of protein nutrition is reviewed. Any such cross-sectional measurement is inherently limited. Using published values for urinary creatinine excretion per kilogram body weight in adult subjects of varying age and values for "ideal" weight as a function of height, we have derived normal values for expected creatinine excretion in men and women of varying height. These permit the derivation of an age-corrected CHI. Possible explanations for the normal decrease in creatinine excretion with age include (1) decreasing lean body mass with age, (2) decreasing proportion of muscle in lean body, and (3) lower meat intake in older persons. Diet has an important influence if meat intake is substantial or if consumption of a creatine-free diet is prolonged. Creatinine metabolism and extrarenal excretion are minor, except in subjects with reduced renal function. Application of a correction for constant extrarenal clearance of creatinine in patients with chronic renal failure probably is not valid. Further observations of creatinine excretion in normal subjects of varying age and height are needed.

During diuresis induced in dogs by water, sodium chloride, sodium bicarbonate, mannitol, glucose, or sucrose, the plasma calcium clearance is, on the average, half the sodium clearance. Free calcium ion clearance therefore equals sodium clearance. This relationship is not altered by reducing calcium or sodium intake, by varying urinary flow or urinary ionic strength, or by varying chloride excretion, independently of sodium excretion. It is only slightly affected by urinary pH, and is not distinctly altered by potassium infusion. Sodium and calcium ions are thus reabsorbed in the proportions in which they are present in plasma. However, previous observations made during sulfate diuresis, when approximately half of the urinary calcium is complexed by sulfate, suggest that the tubular cells tend to maintain a constant ratio of sodium to free calcium ions in the tubular fluid, rather than to reabsorb proportionate quantities of each. It is speculated that this may reflect competitive binding of calcium and sodium at the cell membrane.

1.Creatinine metabolism was studied in nine patients with severe chronic renal failure who were nevertheless in a nearly steady state with respect to their creatinine pool. Labelled creatinine was injected intravenously and the specific radioactivity of creatinine in urine was measured during the ensuing 5-7 days.2. In each patient, the decline in specific radioactivity with time was a single exponential function after 12 h. The volume of distribution of creatinine averaged 49.1 & 2.8% body weight. The average rate of creatinine production was 148 pmol day-' kg-', which is similar to predicted values for normal subjects of the same age, weight and sex. Creatinine metabolism rate/kg body weight, estimated as the difference between production rate/kg body weight, determined radioisotopically, and creatinine appearance rate (excretion plus accumulation), averaged 42 pmol day-' kg-'.3. Total creatinine metabolism rate/kg body weight was correlated with serum creatinine. Thus, as serum creatinine rises, an increasing fraction of the produced creatinine was metabolized rather than excreted. This relationship could account for the diminished creatinine excretion commonly seen in patients with chronic renal failure.4. Extrarenal clearance (metabolism/serum creatinine) of this magnitude (approximately 3 1% Mass. 021 15, U S A . of renal clearance in these patients) would be an undetectably small fraction of normal renal clearance. This could explain the absence of demonstrable creatinine metabolism in normal subjects. 5.Two pathways of metabolism were identified: a recycling of creatinine to creatine and an irreversible degradation of creatinine to products other than creatine.

The total measured concentration of an ionizable constituent of body fluids often fails to reveal either the varied chemical forms in which it may be present, or the portion which is present as the free ionized substance. This truism applies to most organic acids and bases and to inorganic ions which are multivalent. Univalent ions whose corresponding acids and bases are strong may be viewed as exceptions to this generalization. This exclusion is more quantitative than qualitative, since small fractions of these constituents may also be complexed or bound.Plasma and extracellular fluid differ from other body fluids in containing predominantly univalent strong electrolytes. The plasma concentrations of organic acids and bases and of multivalent inorganic ions are relatively low. Nevertheless, the measured concentrations of these substances in plasma may fail to reflect their interactions with one another, and therefore the individual ionic species present.By means of ultrafiltration, a protein-free fluid may be obtained which is probably identical with the protein-free phase in native plasma. This identity is supported by the observation that ultrafiltrate concentrations of calcium (1), magnesium (2) and phosphate (3) do not change during the course of ultrafiltration. In order to quantitate the interactions between nonprotein-bound constituents, one approach is to measure 1) the free ion concentrations of all cations present, 2) the total amount of various anions present, and 3) calculate the amounts of each complex from reported dissociation constants. Undetermined anions will then account for the difference between the total concentration of each cation and the amount accounted for as known complexes. Calcium and magnesium ion concentrations can be * Supported by a United States Public Health Service Grant (A-2306). determined (2). Sodium and potassium are virtually completely ionized. Therefore, this scheme offers promise of analyzing such complex mixtures as plasma, urine and intracellular fluid.In the present report, normal plasma has been analyzed by this procedure with respect to protein, calcium, magnesium, phosphate and citrate. METHODVenous blood was collected without stasis in oiled heparinized syringes from healthy volunteers (medical students, technicians and staff members). Plasma was separated by centrifuging and was stored under oil. Plasma pH was determined promptly at room temperature (230 to 26°C) using a Radiometer pH meter, model 4. No temperature correction was applied. Ultrafiltration was performed as described by Toribara, Terepka and Dewey (1) with two modifications: 1) Visking casing 4 inch in diameter was used, the resulting increase in area for ultrafiltration accelerating the process almost twofold; 2) the strips of casing were soaked in distilled water for 2 days, rinsed, and then stored until used in a chamber saturated with water vapor. Drying in air caused small pinholes to form; use of wet casing, even when thoroughly wiped, led to dilution of ultrafiltrate by water remaining in...

Oral EAAs induce a significant improvement in the serum albumin concentration in hemodialysis but not peritoneal dialysis subjects. Further study of their long-term effects on morbidity and mortality is warranted.