Acidification capacity of the kidneys and aging

The authors studied the acidification capacity of the kidneys in 60 healthy subjects aged 18-70 years after a single load of NH4Cl in a dose of 0.1 g/kg. The acidification load was followed by a significant increase in NH4+ excretion in the first five hours afterwards in young individuals (18-30 years). In subjects aged over 50, changes in NH4+ excretion were nonsignificant under these conditions. Titratable acid excretion rose significantly after the given acidification load in subjects aged 18-60 years; in older subjects it no longer increased significantly. Changes in titratable acid excretion displayed a significant correlation to the renal excretion of phosphates. The findings indicate that the diminished capacity of older subjects to increase titratable acid excretion after an acute NH4Cl load is due to an insufficient decrease in the tubular resorption of phosphates. Renal capacity for adequate reduction of the urine pH after a NH4Cl load was unimpaired.     

Effects of acid challenge on in vivo and in vitro rat renal ammoniagenesis.

This study compares the ability of different strengths of NH₄Cl, CaCl₂, and HCl to affect the termporal excretion of ammonium in rats. Oral NH₄Cl given in a single dose of 0.5 mmole, 1.0 mmole and 1.5 mmole/100 g BW steadily increases ammonium excretion in rats. The majority of the augmented ammonium excretion is secondary to increased renal production — not to changes in urine pH or urine volume. Acute challenges greater than 1.5 mmole/100 g BW do not increase ammonium excretion further. Results were similar when chronic acid challenge was investigated — greater NH₄Cl challenges cause greater ammonium excretion. Challenges beyond 1.5 mmole/100 g BW bid frequently cause death unless the rats are preconditioned (made mildly acidotic) prior to initiation of this dose. At the 1.5 mmole/100 g BW dose, maximal ammonium excretion is reached by day 2 or 3. Thus, maximal renal ammoniagenesis during acid stress occurs rapidly, and at different times depending on the strength of the acid challenge. CaCl₂ or HCl offer no advantages over NH₄Cl as acidifying agents. In addition to the above, there is a significant correlation between ammonium excretion $\text{in vivo}$ and the ability of rat renal slices to produce ammonia from glutamine or glutamate $\text{in vitro}$.     

Importance of medullary events in ammonium excretion: studies in acute respiratory and acute metabolic acidosis

The renal medulla can play an important role in acid excretion by modulating both hydrogen ion secretion in the medullary collecting duct and the medullary PNH3. The purpose of these experiments was to characterize the intrarenal events associated with ammonium excretion in acute acidosis. Cortical events were monitored in two ways: first, the rates of glutamine extraction and ammoniagenesis were assessed by measuring arteriovenous differences and the rate of renal blood flow; second, the biochemical response of the ammoniagenesis pathway was examined by measuring glutamate and 2-oxoglutarate, key renal cortical metabolites in this pathway. There were no significant differences noted in any of these cortical parameters between acute respiratory and metabolic acidosis. Despite a comparable twofold rise in ammonium excretion in both cases, the urine pH, PNH3, and the urine minus blood PCO2 difference (U-B PCO2) were lower during acute hypercapnia. In these experiments, the urine PCO2 was 34 mmHg (1 mmHg = 133.322 Pa) lower than that of the blood during acute respiratory acidosis while the U-B PCO2 was 5 +/- 3 mmHg in acute metabolic acidosis. Thus there were significant differences in medullary events during these two conditions. Although the urine pH is critical in determining ammonium excretion in certain circumstances, these results suggest that regional variations in the medullary PNH3 can modify this relationship.     

Cutaneous and renal responses to intravascular infusions of HCl and NH4Cl in the bullfrog (Rana catesbiana)

This study examined the ability of bullfrogs to correct a non-respiratory acidosis by renal and cutaneous mechanisms. Acidosis was induced by intravascular infusions of HCl (3 mmole/kg) or NH4Cl (4 mmole/kg). The acid load was removed primarily by increased renal excretion of NH4+, while urine pH and titratable buffer acid excretion changed little. Acid loading resulted in an increase in cutaneous permeability, shown by large ion losses and elevated water uptake across the skin. It is concluded that infused mineral acids were immediately buffered by the extracellular fluids, moved rapidly into the intracellular fluid compartment, and only later were slowly cleared.     

The actions of cortisol on fetal renal function

Renal function was studied in 6 fetal sheep, aged 126-135 days, before and after 3 injection of 15 mg of cortisol given at intervals of 12 h. Cortisol caused a significant rise in both renal blood flow (P less than 0.05) and glomerular filtration rate (P less than 0.005), and in urine flow rate (P less than 0.02) but it did not consistently cause a natriuresis. The urinary pH was unchanged following cortisol treatment, but bicarbonate excretion increased. Urinary phosphate excretion was increased (P less than 0.005) because of a rise in filtered phosphate and a fall in phosphate reabsorption. The titratable acid excretion increased (P less than 0.005) but urinary ammonium excretion did not. The total amount of sodium reabsorbed increased after cortisol but the amount of sodium reabsorbed in the proximal tubule did not increase, so fractional reabsorption in the proximal tubule decreased from 61.7 +/- 4.1% to 47.3 +/- 4.2% (P = 0.01). The total amount of sodium reabsorbed in the distal tubule increased and distal fractional reabsorption increased from 33.3 +/- 2.4% to 47.3 +/- 4.2% (P less than 0.01). Cortisol may increase the capacity of the immature kidney to play a role in fluid and electrolyte homeostasis by increasing glomerular filtration rate and delivering more sodium and water to the distal nephron where the reabsorption of sodium and water can be modified independently and in accordance with need.     

Renal excretion of long term sulfonamides under fluid administration and modification of the urinary pH value]

The renal excretion of sulfaclomide, sulfamerazine and sulfamethoxypyridazine is delayed by increased fluid application in rats. The simultaneous administration of sulfonamides and ammonium chloride or sodium hydrogen carbonate causes, respectively, retardation and acceleration of renal sulfonamide excretion which is consistent with the change in urinary pH value. The retarded renal sulfonamide excretion with increasing diuresis is explained by the ensuing change in the urinary pH value. For clinical uses, a speedy renal excretion of long-time sulfonamides by increased diuresis can be expected only if alkalization of the urine is achieved at the same time.     

High Dosage Metolazone in Chronic Renal Failure

Metolazone is a modified quinazolinesulphonamide and in a dose of between 4 and 7·5 mg is an effective diuretic in man with normal renal function. Fourteen patients with non-oedematous stable chronic renal failure (creatinine clearance ranging from 1·2 to 12 ml/min) were given metolazone in doses ranging from 20-150 mg. A noticeable increase in urine flow and sodium excretion occurred, free water clearance increased, and there was a small but significant increase in potassium excretion. No side effects were noted.     

The determination of titratable acid and ammonium ions in picomole amounts

A methodological system mainly designed for the use on intratubular urine samples is described, which permits the determination of titratable acid and ammonium ions in samples of a few nanoliters. The pH measurements were performed by means of antimony micro electrodes, the construction of which are described in detail. The hydroxyl ions were added to the samples from a second antimony electrode system, by an electric current. The amount of hydroxyl ions liberated was equivalent to the amount of current used.The ammonium determinations were based upon the fact that hydrogen ions were liberated from the ammonium ions by formaldehyde. The hydrogen ions were titrated in the same manner as the titratable acid.The use of two electrode systems simultaneously inserted in the droplet permitted recordings of the titration curves. The magnitude of methodological errors of these ultramicro methods are the same as those of corresponding methods using milliliter volumes.     

Silicic acid: its gastrointestinal uptake and urinary excretion in man and effects on aluminium excretion

Silicon (Si), as silicic acid, is suggested to be the natural antidote to aluminium (Al) toxicity, and was recently shown to promote the urinary excretion of Al from body stores. The metabolism of Si in man, however, remains poorly investigated. Here we report on the pharmacokinetics and metabolism of Si in healthy volunteers following ingestion of orthosilicic acid (27-55 mg/l Si) in water. We also investigated whether orthosilicic acid promotes the urinary excretion of endogenous Al. Minimum, median uptake of Si from the ingested dose was 50.3% (range: 21.9-74.7%, n = 8) based on urinary analysis following dosing. Significant correlations were observed between creatinine clearance and Si levels in serum or urine (r = 0.95 and 0.99, respectively). Renal clearance of Si was 82-96 ml/min suggesting high renal filterability. These results suggest that orthosilicic acid is readily absorbed from the gastrointestinal tract of man and then readily excreted in urine. There was no significant increase in Al excretion, over 32 h, following ingestion of the orthosilicic acid dose (P = 0.5; n = 5).     

The Effects of Probenecid and Thiazides and Their Combination on the Urinary Excretion of Electrolytes and on Acid-base Equilibrium

The effects of commonly used therapeutic doses of hydrochlorothiazide and probenecid, given singly and in combination, on the urinary excretion of monovalent and divalent ions and on acid-base equilibrium were studied in four patients with idiopathic hypercalciuria.Probenecid had no effect on the urinary excretion of monovalent ions but resulted in a sustained increase in the urinary excretion of calcium, magnesium and citrate and a temporary increase in the urinary excretion of ammonium, in addition to its well-known effects on uric acid metabolism. A temporary fall in serum phosphorus levels was also observed.Probenecid also modified the response to hydrochlorothiazide in that the urinary excretion of calcium, magnesium and citrate was greater during combined therapy than when hydrochlorothiazide was administered alone. Probenecid prevented or abolished the increase in serum uric acid levels associated with the use of thiazide but did not modify the effects of hydrochlorothiazide on the urinary excretion of sodium, chloride, potassiu, phosphorus, ammonium, titratable acid and bicarbonate.     

Renal regulation of acid-base balance in a freshwater fish (1).

Intra-arterial injection of a fixed acid load caused only a short-lived (less than 2h) disturbance of blood pH but a long lived (2-3 days) elevation of urinary acid excretion in freshwater trout (Salmo gairdneri). The renal response comprised an immediate increase in acid output in the form of titratable acidity minus bicarbonate, and a slower rise in acid output in the form of ammonia. The total elevation in urinary acid efflux over 72h was such that no other mechanism besides renal function is needed to explain the ultimate compensation of this experimental acid-base disturbance.     

Mechanism of enhanced bioavailability and diuretic effect of azosemide by ascorbic acid in rats

To increase the extent of comparative oral bioavailability (F) value and the diuretic and natriuretic effects of orally administered azosemide, ascorbic acid was coadministered to rats. The rationales for this study are that ascorbic acid might inhibit intestinal first-pass effect of azosemide and might increase the unionized fraction of azosemide at the receptor sites. After oral administration of azosemide (20 mg/kg) with 100 mg of ascorbic acid, the F value (138% vs. 100%), 8-h urinary excretion of azosemide (5.18% vs. 1.32% of oral dose), 8-h urine output (41.3 vs. 23.0 ml), and 8-h urinary excretion of sodium (24.6 vs. 15.3 mmol/kg) were greater than controls (without ascorbic acid). The amount of spiked azosemide remaining after 30 min incubation of 50 mug of azosemide with the 9000 g supernatant fraction of rat small intestine was significantly greater by 100 microg of ascorbic acid (45.3 vs. 40.9 microg) than controls (without ascorbic acid). After oral administration of azosemide with NH4Cl, the urine pH decreased by 0.5 U, and 8-h urine output (25.8 vs. 11.0 ml) and 8-h urinary excretion of sodium (13.3 vs. 6.89 mmol/kg) were significantly greater than controls (without NH4Cl). The increase in F value and diuretic and natriuretic effects of azosemide with coadministration of ascorbic acid seemed to be due to reduced intestinal first-pass metabolism of azosemide, increased urinary excretion of azosemide, and increased unionized fraction of azosemide at the renal tubular receptor sites.     

Influence of Medetomidine on Acid-base Balance and Urine Excretion in Goats

Seven goats were given medetomidine 5 μg/kg as an iv bolus injection. Venous blood samples were taken repeatedly and urine was collected continuously via a catheter up to 7h after the injection. Medetomidine caused deep clinical sedation. Base excess, pH and PCO2 in venous blood rose after medetomidine administration. There were no significant changes in plasma concentrations of sodium, calcium, magnesium, creatinine or osmolality, whereas potassium and bicarbonate concentrations increased, and phosphate and chloride decreased. Medetomidine increased plasma glucose concentration, and in 4 of 7 goats glucose could also be detected in urine. Medetomidine did not influence urine flow rate, free water clearance, bicarbonate and phosphate excretion or pH, but renal chloride, sodium, potassium, calcium, magnesium and creatinine excretion were reduced. The results suggest that the metabolic alkalosis recorded after medetomidine administration is not caused by increased renal acid excretion.     

Effect of supplementation with L-carnitine at a small dose on acylcarnitine profiles in serum and urine and the renal handling of acylcarnitines in a patient with multiple acyl-coenzyme A dehydrogenation defect

We studied the effects of L-carnitine supplementation at a small dose on the profiles of acylcarnitines in serum and urine, as well as the renal handling of acylcarnitines, in a patient with multiple acyl-coenzyme A dehydrogenation defect. After supplementation with L-carnitine at a dose of 20 mg/kg/day, the concentration of each acylcarnitine measured both in the serum and in the urine had increased significantly, with the exception of that of an acylcarnitine with a carbon chain length (C) of 8 (C8 acylcarnitine). The magnitude of increase in the concentrations of the acylcarnitines in the serum was not associated with chain length, whereas in the urine, the magnitude tended to be greater in proportion to the shortness of the chain length. The fractional excretions of C2-C5 acylcarnitines exceeded 100%, indicating that they were produced in, or transported across, renal tubular epithelial cells and secreted into the urine. These results indicate that supplementation with a relatively small amount of L-carnitine can enhance the renal excretion of accumulated short-chain-length acylcarnitines through tubular excretion, in addition to basic glomerular filtration.     

Renal ammonium production--une vue canadienne

The purpose of this review is to examine the factors regulating ammonium production in the kidney and to place these factors in the perspective of acid-base balance. Renal ammonium production and excretion are required to maintain acid-base balance. However, only a portion of renal ammonium production is specifically stimulated by metabolic acidosis. One should examine urinary ammonium excretion at three levels: distribution of ammonium between blood and urine, augmented glutamine metabolism, and an energy constraint due to ATP balance considerations. With respect to the biochemical regulation of acid-base renal ammonium production, an acute stimulation of alpha-ketoglutarate dehydrogenase by a fall in pH seems to be important but this may not be the entire story. In chronic metabolic acidosis augmented glutamine entry into mitochondria (dog) or increased phosphate-dependent glutaminase activity (rat) become critical to support a high flux rate. Metabolic alterations, which diminish the rate of oxidation of alternate fuels, might also be important. The above principles are discussed in the ketoacidosis of fasting, the clinically important situation of high rates of renal ammonium production.     

Ferulic acid excretion as a marker of consumption of a French maritime pine (Pinus maritima) bark extract

French maritime pine (Pinus maritima) bark extract (PBE) is a polyphenol-rich food supplement patented under the name of Pycnogenol and known to have strong antioxidant activity and different beneficial effects on human health. Although its biological properties have begun to be extensively studied both in vitro, in laboratory animals and more recently in humans, little is known about its bioavailability. The present study investigated the urinary excretion of free and conjugated ferulic acid, present in quantitatively detectable amounts in PBE, after oral PBE administration to human subjects. Eleven healthy adult subjects (4 women and 7men) consumed either a single dose (200 mg PBE) or two doses of PBE (100 and 200 mg, respectively) within a 48-h interval. Two days before the oral administration of PBE and during the urine sample collection period volunteers adhered to a diet low in polyphenols. Aliquots of all urine production were collected over 24 h. Free and conjugated ferulic acid was assessed in urine by HPLC using diode array detection. A close association between the dietary intake of PBE and the urinary excretion of ferulic acid was detected. Moreover, the results indicate that a considerable proportion of ferulic acid is excreted as glucuronide or sulfate after PBE consumption, varying over the range 2 to 20% between individuals. The kinetics of excretion associated with the administration of 100 mg PBE was quite similar to that obtained after 200 mg PBE. A a biphasic trend was evident in a number of subjects. All subjects studied here displayed a significant, although variable level of excretion of ferulic acid after supplementation with PBE, Thus, the data provide evidence that at least a part of the phenolic components of PBE are absorbed, metabolized, and eliminated by humans.     

Effect of nifedipine on kidney output of calcium, oxalic acid, and saturation of urinary calcium oxalate]

The study involved 30 patients treated with nifedipine in daily dose of 30 mg for 7 days. Calcium, magnesium, phosphate, oxalate, and uric acid levels in the urine were measured. It was found that nifedipine significantly decreased oxaluria urinary excretion of calcium, magnesium, phosphate, and uric acid remained unchanged following nifedipine therapy. Results may suggest that nifedipine may exert an influence on renal stone formation.     

Renal response to secretin.

The effect of Jorpes secretin on the urinary volume, pH, and excretion of sodium, potassium, chloride, bicarbonate, titratable acidity, ammonia and phosphate was studied in five healthy male volunteers with and without simultaneous aspiration of duodenal fluids. A three- to fourfold increase in urinary volume and sodium excretion occurred within the first 30 min after secretin injection and this was accompanied by a significant rise in urinary pH in each instance. Urinary bicarbonate excretion increased from 55 plus or minus 13 to 395 plus or minus 33 mueq/30 min after secretin injection. Aspiration of alkaline duodenal contents was accompanied by an even greater postsecretin increase in urinary bicarbonate excretion. No significant changes in arterial pH or blood gases were detected throughout the study. These observations are compatible with a direct effect of secretin upon the renal tubular reabsorption of water, bicarbonate, and other ions, and could account for the transient alterations in urinary pH occurring in response to a meal.     

Renal Excretion of Digoxin in Swine and Goats

In experiments on swine and goats the renal excretion of digoxin was examined, and it was found that the renal clearance of non-protein-bound digoxin in swine was lower than creatinine clearance which expresses filtration clearance. Correlation analysis showed that the renal clearance of digoxin in swine was not significantly influenced by the concentration of non-protein-bound digoxin in plasma and the pH of the urine, while there was a significant positive correlation between the clearance and the urine flow rate (Table 4). On the other hand, the renal clearance of digoxin in goats was significantly influenced by the concentration of non-proteinbound digoxin in plasma and by urine pH (Table 4). From these results it is concluded that glomerular filtration and back-diffusion are involved in the renal handling of digoxin in both swine and goats. In addition active tubular secretion is also involved in the renal excretion of digoxin in goats.     

Effect of acetylsalicylic acid on urinary excretion of prostaglandin E in stroke patients

In 12 of 76 stroke patients complicated by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), a significant increase in urinary prostaglandin E (PGE) (p less than 0.005), and a significant positive relationship between the plasma arginine vasopressin (AVR) level and urinary PGE excretion were observed (r = 0.72, p less than 0.05). The experimental results are consistent with the view that renal PGE acts as a modulator of ADH. Nowadays acetylsalicylic acid (ASA), an inhibitor of prostaglandin biosynthesis, is widely used in ischemic stroke, it was felt necessary to study the effect of this drug on urinary PGE excretion. Therefore various daily doses of ASA were given orally for 3 days to patients with ischemic stroke. PGE values in 24-hour urine samples were measured every day for 3 days before administration of the drug and for 3 days during ASA administration. In 10 patients who took 75 mg of ASA, the decrease in urinary PGE excretion was not statistically significant. On the other hand when ASA was administered 300 mg once in 19 patients or 300 mg 4 times in 11 cases, urinary PGE excretion decreased significantly (p less than 0.05 and p less than 0.05 respectively). In another group of 8 patients who were observed before, during and after the ASA administration, a daily oral dose of 300 mg for 3 days caused a significant decrease in urinary PGE excretion during these 3 days (p less than 0.05). The urinary PGE excretion returned to the control level within 3 days after cessation of the ASA administration.