Urinary Ammonium Excretion Research Articles

Intermediary metabolism of the mature rat following 2,3,7,8-tetrachlorodibenzo- p-dioxin treatment

Changes in body weight, feed intake, hepatic cellularity, and intermediary metabolism were assessed in the mature male (450 g) rat following 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) administration. All animals were schedule-fed (8-hr feeding period/24 hr) and treated with a single oral dose of either TCDD (75 μg/kg) or vehicle. Blood and tissues were sampled 16 to 18 hr following the end of the feeding period on 2, 4, 6, and 8 days post-treatment. Mature rats treated with TCDD exhibited a slight but progressive reduction in both body weight and feed intake throughout the 8-day experimental period. An increase in liver mass that was apparent at 2 days and plateaued by 4 days after TCDD treatment was associated with a decrease in the concentration of DNA per gram of wet liver. However, the total liver content of DNA in TCDD-treated rats remained similar to pair-fed animals. Thus, TCDD treatment produced liver enlargement in the mature rat that was the result of hepatocellular hypertrophy and not an increase in cell number. Hepatic glycogen content in TCDD-treated rats was threefold higher than their pair-fed counterparts at 2 to 6 days post-treatment, and this augmentation would account, in part, for the hypertrophy of the liver cell found after administration of TCDD. Plasma glucose and lactate concentrations were similar in TCDD-treated and pair-fed rats, suggesting that the Cori cycle remained unaltered following TCDD administration. Likewise, heart and gastrocnemius glycogen concentrations were similar in all experimental groups. Urinary excretion of urea, ammonia, and creatinine was comparable in TCDD-treated rats and their pair-fed counterparts, indicative of a nitrogen balance that was not disturbed by TCDD. Plasma glutamine concentrations in TCDD-treated rats tended to be reduced and were significantly lower at Day 6 post-treatment when compared to those of pair-fed counterparts, suggestive that amino acid release from muscle was not enhanced in TCDD-treated rats. Likewise, plasma concentrations of branchedchain amino acids, which are metabolized to a large extent in muscle, tended to be lower on Day 6 following TCDD treatment. Yet at Day 6 post-treatment, the circulating concentrations of amino acids that are metabolized by the liver were elevated in TCDD-treated animals. TCDD administration also resulted in an increase in total hepatic protein concentration which was evident at 4 days and increased progressively at 6 and 8 days post-treatment. Liver content of phospholipids also increased gradually following administration of TCDD. Enhanced accumulation of phospholipid and protein in the liver, most probably as a result of increased membrane formation, would contribute not only to the hepatocellular hypertrophy but also the hepatomegaly. The content of triacylglycerols in both liver and plasma of TCDD-treated rats was elevated at Day 2 and remained elevated throughout Day 8 post-treatment. The similar time course and extent of the augmentation of triacylglycerols in both plasma and liver would imply that the secretion of triacylglycerol-rich lipoproteins from the liver of TCDD-treated rats was not restricted. Thus, administration of TCDD to the mature rat enhanced hepatic esterification of fatty acids into both triacylglycerols and phospholipids at least up to 8 days post-treatment. The decreased plasma concentration of total ketone bodies is also compatible with a diminution of fatty acid oxidation and an increased esterification in the liver of TCDD-treated rats. Thus, TCDD caused selective alterations in hepatic carbohydrate, protein, and lipid metabolism that were not secondary to reduced caloric intake.

Time course of urinary excretion of intraportal ammonia as uric acid and ammonia in chickens fed low- or high-protein diet

1. 1. 15N-ammonia was intraportally infused for 6hr into chickens fed 5% or 20% protein diet to examine the time course of urinary excretion of intraportal ammonia and dietary effects on it. 2. 2. Urinary ammonia increased linearly for the first hour to the same extent in both dietary groups and thereafter further in the low-protein group. 3. 3. Urinary uric acid derived from the intraportal ammonia adaptively increased and reached a steady state level within 1.5hr. This level was four times higher in the high-protein group. 4. 4. The infused ammonia was excreted into urine as both ammonia and uric acid, in relatively high proportions in the chickens fed the low-protein diet but was almost all excreted as uric acid in those fed the high-protein diet.

Net tubular secretion of bicarbonate by the alligator kidney. Antimammalian response to acetazolamide

Net tubular secretion of bicarbonate by the alligator kidney was demonstrated during acute clearance experiments where the animals were infused with an isosmotic solution of one-half 5% mannitol and one-half 0.9% NaCl. Tubular secretion of bicarbonate averaged 3.38 mumoles/min in animals with a mean wt of 1.0 kg. During these experiments, mean tubular secretion of urate was 0.51 mumole/min and urinary ammonia excretion was 4.3 mumoles/min. Urinary pNH3 was high and ranged from 22,231 to 41,223 mm Hg X 10(-6). The administration of acetazolamide 25 mg/kg resulted in abolition of bicarbonate secretion, which was replaced by bicarbonate reabsorption. At the same time, the tubular secretion of urate fell by 70% and the excretion of ammonia fell by 77%. This is the first time that net tubular secretion of bicarbonate is demonstrated in a living animal. Acetazolamide has an antimammalian effect. It is proposed that the alligator that lives with a low plasma bicarbonate concentration (10 mM) possesses a kidney in which the renal tubular cells secrete bicarbonate in the tubular lumen and hydrogen at the peritubular site, in contrast to that which takes place in mammalia and other animal species.

Tubular action of diuretics: Distal effects on electrolyte transport and acidification

We used clearance and free-flow micropuncture techniques to evaluate the influence of several diuretic agents, given both individually and in various combinations, on transport of sodium, potassium, and fluid, and on acidification and ammonium transport, within the distal tubule of the rat kidney. The loop diuretics, furosemide and piretanide, sharply increased fractional delivery of fluid, sodium, and potassium into the distal tubule, and, as a result, sodium reabsorption and potassium secretion were enhanced in this nephron segment. These two drugs also stimulated urinary acidification and increased urinary phosphate, titratable acid, and ammonium excretion. These effects took place both within the loop of Henle and along the distal tubule. Amiloride and triamterene alone inhibited distal tubular sodium reabsorption and potassium secretion, and, when given with one of the loop diuretics, suppressed both the kaliuresis and the increased acid and ammonium excretion induced by the latter agents. Hydrochlorothiazide and tizolemide inhibited sodium reabsorption within the distal tubule, and were associated with a stimulation of potassium secretion within this segment. Addition of one of these two latter distally acting agents to either of the loop diuretics led to a further augmentation of sodium excretion, but to a reduction of potassium excretion, compared to the responses seen after the loop diuretics alone.

Renal tubular biochemistry during acute and chronic metabolic alkalosis in the dog

Acute metabolic alkalosis was induced in dogs by the infusion of sodium bicarbonate, 0.3 M. Chronic alkalosis was induced by chloride restriction and the administration of sodium bicarbonate and furosemide. In a third group of dogs, potassium was added to the regimen to prevent frank potassium depletion. Plasma bicarbonate ranged from 29.0 to 32.9 mM. In all three dog groups, renal ammoniagenesis fell by over 30%, which was consistent with a decrease in the renal uptake of glutamine. Glutamate was released in the renal vein and alanine production was decreased. Total production of ammonia was lowest in the animals given a potassium supplement where muscle potassium decreased much less than in the other chronic animals. Urinary ammonia excretion was very low in all three animal groups; this was related to an alkaline urine. However, this relationship was not entirely consistent and the low excretion of ammonia could also be related to decreased ammonia production by the renal tubular cell. In the renal cortical tissue (freeze-clamped), the concentration of glutamate did not change and that of alpha-ketoglutarate rose only in the animals supplemented with potassium. Malate rose in all groups. In all animals, renal tissue concentration of lactate and citrate rose while citrate excretion increased. We feel that glycolysis could play an important role in renal metabolism during acute and chronic metabolic alkalosis. We have proposed a unified theory to explain the metabolic changes that occur in lactate and citrate metabolism during metabolic alkalosis with a depressing effect on ammoniagenesis. Although citrate could be generated in the mitochondria from pyruvate, its oxidation is probably inhibited with exit and accumulation in the cytosol.

Effect of cortical-medullary gradient for ammonia on urinary excretion of ammonia

Previous studies suggested that a portion of ammonia secreted into the proximal tubule may diffuse directly from Henle's loop into the medullary collecting duct. Since water is absorbed along the course of the descending portion of the loop, it was proposed that the concentration of ammonia increased in loop fluid, and that rapid diffusibility of the free base would facilitate the delivery of ammonia into medullary interstitium where a high level could be maintained by the countercurrent exchange process. In this schema it was proposed that there was an ammonia concentration gradient between medullary structures and cortex, and recovery of ammonia by the medullary collecting duct due to the low pH in tubule fluid at that site. The present study was designed to evaluate this hypothesis by estimating ammonia concentrations in medullary and cortical tissue, and by correlating medullary levels with secretion rate into the inner medullary collecting duct. In control animals the concentration of total ammonia (NH4+ + NH3+) in inner medullary vasa recta was 9.2 +/- 1.5 mumoles/ml, a level 100-fold higher than the cortical level of 0.10 +/- 0.01. During acute acidosis the medullary level rose to 22.5 +/- 2.7 mumoles/ml, but in acute acidosis during mannitol infusion the level fell to 8.0 +/- 1.2. The rate of ammonia secretion into inner medullary collecting duct fluid correlated directly with medullary vasa recta ammonia concentration. These data provide evidence for a steep ammonia concentration gradient between the medulla and cortex, and suggest that the diffusion gradient across collecting duct epithelium governs the rate of the addition of ammonia to collecting duct fluid.

Apparent compartmentation of body nitrogen in one human subject: its consequences in measuring the rate of whole-body protein synthesis with 15N.

The rate of protein synthesis in the whole body was measured in one fed subject with seven 15N-labelled amino acids (intravenous and oral doses) and two 15N protein mixtures (oral doses only). The rates were determined individually from the urinary excretion of ammonia and total urea over a 12 h experimental period. Except with oral glycine and alanine, the synthesis rates given by ammonia and urea were appreciably different within each study when calculated on the assumption of a single pool of metabolic nitrogen in the body. In general, intravenous administration of the tracers gave higher rates with urea and the oral route gave higher rates with ammonia. The differences between intravenous and oral doses of 15N could be reduced significantly by calculating synthesis rates from either the arithmetic or harmonic average of flux rates given by ammonia and urea. The averages correspond to estimates of the total flux in a two-pool model of metabolic nitrogen when it is assumed either that both pools receive an equal amount of tracer (arithmetic) or that both have the same rate of nitrogen turnover (harmonic). By so reducing the effect of physical separation of nitrogen in the body, the metabolic aspects of compartmentation of the tracer could be examined. The results show that the absolute value obtained for protein synthesis depends on the source of labelled nitrogen. The data are discussed in this empirical context.

Familiar Hyperkalaemic Acidosis<xref ref-type="fn" rid="fn2"><sup>†</sup></xref>

We evaluated a 26-year-old man with hyperkalaemic acidosis, apparently inherited as an autosomal dominant trait. Type II pseudohypoaldosteronism was suggested by normal aldosterone production and renal sodium conservation. The cause of acidosis in this syndrome is unknown. Both urinary ammonium excretion and bicarbonate threshold were low during hyperkalaemia. After correcting the hyperkalaemia ammonium excretion was normal, but bicarbonate threshold remained low. Maximum bicarbonate reabsorption, urine to blood pCO2 gradients, and minimum urine pH were normal. These findings suggest that hyperkalaemia might contribute to the acidosis by limiting urinary buffer, but that the primary defect is reduced mineralocorticoid effect on hydrogen ion secretion. When the poorly reabsorbed anion, sulphate, was infused, hydrogen ion and potassium secretion were normal. When the relatively reabsorbable anion, chloride, was infused, potassium secretion was decreased. These findings suggest that the attenuated mineralocorticoid effect on hydrogen ion secretion is due to increased reabsorptive avidity for chloride in the distal nephron. To determine if this defect caused resistance to mineralocorticoid we increased mineralocorticoid by dietary sodium restriction and later administered desoxycorticosterone and fludrocortisone. Both endogenous and exogenous mineralocorticoid caused increased net acid excretion and corrected the acidosis, indicating no resistance to mineralocorticoid. Hydrochlorothiazide 50 mg daily promptly corrected the acidosis and the hyperkalaemia by increased urinary potassium excretion. We conclude that the acidosis of type II pseudohypoaldosteronism is due in part to attenuation of the voltage-dependent moiety of mineralocorticoid-driven acidification caused by enhanced distal chloride reabsorption. Suppression of ammoniagenesis by hyperkalaemia exaggerates the acidosis. The acidosis and hyperkalemia are corrected by hydrochlorothiazide.

Ammonia production and amino acid metabolism by rat renal papillary epithelial cells in culture.

A significant percentage of excreted ammonium is added to tubular fluid along the medullary collecting duct. However, it is not clear whether this ammonia is produced in the cortex and delivered into the medulla or is produced directly by medullary cells. To address this issue, rat epithelial cells derived from the renal papilla were grown in continuous culture and their ability to generate ammonia was examined. When grown in Dulbecco's modified Eagle's medium with 4 mM glutamine, these cells produced ammonia at a rate of approximately 27 nmol/10(6) cells/h. When these cells were grown in minimum essential medium without glutamine, ammonia production fell to 7 nmol/10(6) cells/ h. Increasing the glutamine concentrations of minimum essential medium to 4 mM increased ammonia production to slightly greater than 30 nmol/10(6) cells/ h. Increasing the media concentration of glutamate, glycine, or asparagine resulted in no significant increase in ammoniagenesis. Analysis of media amino acid concentration revealed that glutamine was the main amino acid consumed while alanine was the predominant amino acid produced. The glutaminase activity of these cells appears to be primarily phosphate-dependent, similar to that observed in vitro in papillary tubules. Alterations of K+ or H+ ion concentration did not alter ammoniagenesis, but addition of 2.5 mM ammonium chloride significantly reduced net ammonia production. It is concluded that rat papillary epithelial cells have the intrinsic ability to utilize glutamine to generate ammonia and alanine. In vivo ammonia produced locally in the medulla may contribute to final urinary ammonium excretion.

Choline requirement of the preruminant lamb during the first two or three weeks of life

Preruminant male crossbred lambs, aged 1-2 days at the start of the experiment, were bottle-fed on milk replacers containing casein as the sole source of protein for an experimental period of 15-21 days. Choline-deficient diets were used in experiment 1 to determine the effect on the performance of the lambs of thc dictary protein concentration (10, 15 and 25% protein energy), and in experiment 2 of different sources of fat (butter oil, maize oil or lard), unsupplemented, or with supplements of choline chloride or L-cystine. Supplements of choline chloride decreased liver fat content and decreased urinary creatine excretion, irrespective of dietary protein concentration or source of dietary fat. Ira general, urinary ammonia excretion increased as the sulfur amino acid content of the diets increased, but there were interactions with the source of fat, so that although sulfur intake remained constant ammonia excretion was higher with diets containing lard than with those containing maize oil or butter oil. The effect of the supplements of 1,-cystine on liver fat content and urinary creatine excretion was not significantly different from that of the unsupplemented choline-deficient diets. In experiments 3 and 4 a choline-deficient diet with 25% protein energy and butter oil as the source of fat was supplemented with graded amounts of choline chloride. Energy intake was ad libitum, or restricted to 80% of ad libitum. When the lambs were fed ad libitum there was a significant decrease in liver fat content even with the smallest supplement of choline chloride (c. 9 mg MJ-1 gross energy), but no significant effect when energy intake was restricted. Since liveweight gains and nitrogen balances were unaffected by the presence or absence of the choline supplements it was concluded that in milk replacers containing 25% protein energy from casein, with butter oil as the source of fat, supplementation with choline chloride to provide 9 mg MJ-1 gross energy (233 mg kg-1 dry matter) would be sufficient to prevent the increased deposition of fat in the liver during the 6rst three weeks of life.

Increased ammoniagenesis and the renal tubular effects of potassium depletion.

The cause of the morphological changes and functional defects in the renal tubule seen in patients with severe potassium depletion is unknown. In man and animals potassium status is a major factor regulating ammonia synthesis in the kidney and urinary ammonium excretion. A primary effect of potassium depletion is to cause an increase in ammoniagenesis by the renal tubular cells. It is proposed that the vacuolation of the renal tubular cells and the functional defects of tubular proteinuria, polyuria, resistance to arginine vasopressin, renal resistance to the action of parathyroid hormone, and increased urinary excretion of N-acetyl-beta-glucosaminidase found in potassium depletion are secondary effects caused by high concentrations of ammonia in the renal tubular cells.

Atrophy and growth failure of rat hindlimb muscles in tail-cast suspension.

Atrophy and growth failure of muscle in a tail-cast suspension model were evaluated in hindlimbs of female Sprague-Dawley rats. Based on measurements of food consumption, animal growth rate, urinary excretion of urea and ammonia, and muscle size, 6 days seemed to be the optimum duration of suspension for studying muscle unloading. After 6 days, the soleus, plantaris, and gastrocnemius muscles from suspended animals were 27, 10, and 11% smaller (P less than 0.05), respectively, than those from tail-casted weight-bearing animals. The extensor digitorum longus and tibialis anterior muscles were unaffected by suspension (less than or equal to 6 days) while the triceps brachii hypertrophied (8%, P less than 0.05). Wet weight-to-dry weight ratios were smaller in the plantaris (-0.19, P less than 0.05) and gastrocnemius (-0.19, P less than 0.05) muscles from suspended rats. In the plantaris, this difference coincided with a higher protein concentration (+12 mg/g, P less than 0.001). In vitro measurements of protein metabolism in the soleus muscles of suspended rats showed both slower protein synthesis (P less than 0.05) and faster protein degradation (P less than 0.05), whereas these processes were unaltered in the extensor digitorum longus muscles.

Metabolic alkalosis during immobilization in monkeys (M. nemestrina).

We studied the systemic and renal acid-base response of monkeys during ten weeks of immobilization. By three weeks of immobilization, arterial pH and bicarbonate concentrations were elevated (chronic metabolic alkalosis). Net urinary acid excretion increased in immobilized animals. Urinary bicarbonate excretion decreased during the first three weeks of immobilization, and then returned to control levels. Sustained increases in urinary ammonium excretion were seen throughout the time duration of immobilization. Neither potassium depletion nor hypokalemia was observed. Most parameters returned promptly to the normal range during the first week of recovery. Factors tentatively associated with changes in acid-base status of monkeys include contraction of extracellular fluid volume, retention of bicarbonate, increased acid excretion, and possible participation of extrarenal buffers.

Ammonium transport in rat cortical tubule: relationship to potassium metabolism.

Free-flow micropuncture studies were carried out in rats to study the relationship between ammonium and potassium transport along superficial nephrons. Proximal and distal tubular fluid was analyzed for [3H]inulin, potassium, and ammonium. Ammonium was measured by a titrimetric formaldehyde method using a glass electrode to measure pH and an antimony electrode to deliver OH ions. In addition to experiments carried out under control conditions, the rats were also acutely potassium loaded, chronically potassium depleted, or given glutamine intravenously to stimulate ammonium excretion. Ammonium production along the proximal tubule was sharply enhanced in potassium depletion and, most likely, also following glutamine infusion, but it remained unchanged during hyperkalemia. Significant amounts of ammonium were lost along the loop of Henle in all experimental conditions. During stimulation of ammonium excretion by either potassium depletion or glutamine infusion the urine became alkaline. No loss or gain of ammonium beyond the late distal tubule was observed in any of the experimental conditions. With respect to potassium transport the glutamine-induced rise in urinary ammonium excretion was associated with stimulation of potassium reabsorption beyond the late distal tubule.

Amino acid-induced hypercalciuria in patients on total parenteral nutrition

Ingestion of protein is known to increase urinary calcium excretion. By studying the effect of intravenous amino acid infusion on calcium excretion, the variables of diets and intestinal absorption are avoided. Five patients on total parenteral nutrition with otherwise constant nutrient infusions containing 240 mg of calcium were randomized to two different levels of amino acid infusion. On 1 g/kg ideal body weight amino acid infusion, two patients excreted more than 240 mg of calcium in the urine, while on 2 g/kg ideal body weight amino acid infusion all five patients lost more calcium in urine than was infused. Mean urinary calcium excretion was increased from 287 to 455 mg/day. On the higher amino acid dose, mean glomerular filtration rate increased from 102 to 143 ml/min. There was no effect of amino acid dose on serum calcium, ionized calcium, parathyroid hormone, and 25 (OH) vitamin D. Calcium excretion corrected for the glomerular filtration rate was increased at the higher amino acid dose, indicating a decrease in renal calcium reabsorption. Daily urinary excretion of sulfate, ammonia, and titratable acidity were increased during the high amino acid infusion. Hypercalciuria induced by high levels of amino acid infusion during total parenteral nutrition may contribute to the development of metabolic bone disease.

Ammonia and Acid-Base Homeostasis

The metabolic pathways involved in renal ammonia production have been considered and potential sites of regulatory control have been delineated. New information that acute acidosis stimulates renal ammonia production and that chronic respiratory acidosis does not result in an adaptive increase in the renal capacity to produce ammonia has been emphasized. The effect of potassium on renal ammonia production and the physiologic and pathophysiologic implication of this relationship have been detailed. Finally, the mechanism of urinary ammonium excretion and the impact of altered ammoniagenesis on urinary acidification, and the interpretation of clinical acidification tests have been discussed.

Dietary Minerals Modify the Food Intake Suppressing Effects of High Casein Diets Fed to Rats

Food intake, growth, and urinary urea and ammonia excretion were studied in young rats undergoing adaptation to high protein diets (70% casein) containing varying amounts of potassium, sodium and chloride. Two commercial mineral mixtures were used. The Bernhart-Tomarelli (BT) mineral mixture is low in K, Na and Cl compared to the TD (modified Williams-Briggs) mineral mixture. Rats consumed significantly less food and had poor growth when fed 70% casein diets containing the BT mineral mixture. Food intake and feed efficiency improved significantly when the BT diets were supplemented with KCl and NaCl, Na acetate or K acetate but not 3-chloropropionate. Urinary urea and ammonia excretion were directly proportional to food (protein) intake. However, body weight gain during the last 3 days of the 9-day study (experiment 3) was negatively correlated with urinary ammonia nitrogen (milligrams per gram food eaten) but not with urinary urea nitrogen. It is concluded that dietary K and/or Na content affects food consumption in rats fed high casein diets. Alterations in renal capacity for handling ammonia may be responsible for the food intake enhancing effect of K or Na in rats fed a high casein diet.high casein diet mineral mixture potassium sodium urinary ammonia food intake

Severe Hypertension, Hyperkalemia, and Renal Tubular Acidosis Responding to Dietary Sodium Restriction

A 13-year-old girl with severe hypertension (240/140 mm Hg), short stature, marked hyperkalemia (8.6 mEq/liter), and renal tubular acidosis was studied. Renal parenchymal and renovascular diseases as well as endocrinologic causes of hypertension were ruled out by appropriate studies. The hypertension was associated with sodium retention, increased plasma volume, suppressed plasma renin activity, and decreased urinary excretion of aldosterone. Impaired renal excretion of potassium was demonstrated by sodium sulfate infusion when the patient was fed a high-sodium diet but a significant kaliuresis occurred when the test was performed on a low-sodium diet suggesting that renal sodium retention may play a role in the defect in potassium excretion. The renal tubular acidosis was associated with normal distal acidification but a low bicarbonate threshold (19 mmoles/liter) and marked suppression of urinary ammonium excretion. The hypertension, hyporeninemia, and hypoaldosteronism as well as the hyperkalemia and acid-base abnormalities were completely reversed by dietary sodium restriction or the administration of thiazides or furosemide. It is concluded that an unusual avidity for sodium chloride reabsorption by the renal tubules leading to extracellular volume expansion and renin-aldosterone suppression plays a significant pathogenic role in this syndrome and may explain the hypertension and biochemical abnormalities discussed.

Ammonia metabolism in Reye syndrome and the effect of citrulline

Ammonia metabolism in Reye syndrome was studied by quantitative analysis of the time course of hyperammonemia and the urinary excretion of ammonia, urea, and total nitrogen. These measures were then utilized to assess the effect of citrulline administration in 8 patients compared to results in 22 patients managed without citrulline. Two indices of the severity and duration of hyperammonemia correlated strongly with mortality: the half-time for decline of hyperammonemia and the area under the hyperammonemia curve (an index of the total burden of ammonia presented to the brain). These results suggest that the total amount of ammonia delivered to brain may be important to the pathogenesis of encephalopathy. Citrulline-treated patients had more severe disease at admission and greater abnormalities in indices of nitrogen and ammonia metabolism, though the latter did not reach significance. The urine ammonia/urea nitrogen excretion ratio, an index of the efficiency of ammonia conversion to urea, normalized more rapidly in the citrulline-treated group, evidence that citrulline may have improved urea cycle function. Overall mortality did not differ in the two groups. The deaths of 2 citrulline-treated patients in this small group were attributable to factors unrelated to treatment, however, so the possible effect of citrulline on mortality was not definitively tested. No indication was found that citrulline was harmful, nor that it increased ammonia levels.

Renal ammoniagenesis in an early stage of metabolic acidosis in man.

Total renal ammonia production and ammonia precursor utilization were evaluated in patients under normal acid-base balance and in patients with 24-h NH4Cl acidosis by measuring (a) ammonia excreted with urine and that added to renal venous blood, and (b) amino acid exchange across the kidney. In 24-h acidosis not only urinary ammonia excretion is increased, but also total ammonia production is augmented (P less than 0.005) in comparison with controls. By evaluating the individual role of acid-base parameters, urine pH and urine flow in influencing renal ammonia production, it was shown that the degree of acidosis and urine flow are likely major factors stimulating ammoniagenesis. Both urine pH and urine flow are determinant in the preferential shift of ammonia into urine. In 1-d acidosis, renal extraction of glutamine was not increased and the total ammonia produced/glutamine N extracted ratio was higher than in controls (P less than 0.005) and was inversely correlated with the log of arterial bicarbonate concentration (P less than 0.001). In the same condition, renal glycine and ornithine uptake took place; the more severe the acidosis, the greater was the renal extraction of these amino acids (P less than 0.001). These data indicate that at the early stages of metabolic acidosis, in spite of a brisk increase in ammonia production, the mechanisms responsible for the increased glutamine use, which are operative in chronic acidosis, are not activated and other ammonia precursors, besides glutamine, are probably used for ammonia production.