André Gougoux

Hypoxemia During Hemodialysis: A Critical Review of the Facts

The literature describing the fall in PaO2 during dialysis is intensively and critically reviewed. This phenomenon is related to both the type of membrane used (cellulosic v noncellulosic membrane), and to the composition of the dialysate (acetate v bicarbonate). It appears that a ventilation/perfusion mismatch due to pulmonary leukostasis can, in part, explain hypoxemia in patients dialyzed with cellulosic membranes. This phenomenon is especially apparent in patients with preexisting pulmonary abnormalities. However, hypoventilation remains the major cause of hypoxemia. This hypoventilation is mainly due to CO2 consumption during acetate metabolism (acetate dialysis), or alkalinization of the blood (bicarbonate dialysis). The metabolic consequences of acetate metabolism, and of bicarbonate and CO2 losses through the dialyzer are critically analyzed. The cause for the increment in oxygen consumption during acetate dialysis is examined. Finally, the respective role of these combined factors are described and used to explain the changes in VCO2, VO2, respiratory quotient (RQ), and PaO2 reported in the literature during dialysis against acetate and/or bicarbonate.

Metabolic changes in skeletal muscle during chronic metabolic acidosis.

1. 1. In an attempt to clarify the importance of skeletal muscle as a source of glutamine during chronic metabolic acidosis, in vivo and in vitro experiments were performed in normal and NH4Cl acidotic rats. 2. 2. In the acidotic animals, arterial glutamine, glutamate and alanine were significantly lower than in normal rats. The arterio-venous difference for glutamine across the hindlimb was not statistically different in acidotic and normal animals. 3. 3. No net release or uptake of glutamate was observed in either control or acidotic rats. However the uptake of alanine observed in normal animals was completely abolished in the acidotic rats. 4. 4. The metabolite profile of freeze-clamped hindlimb skeletal muscle from acidotic animals revealed a lower concentration of glutamine, glutamate, alanine, aspartate, alphaketoglutarate, lactate and pyruvate and increased ammonia concentration. 5. 5. Alanine aminotransferase activity of the hindlimb skeletal muscle was unchanged by acidosis. 6. 6. In vitro glutamine production by the isolated rat diaphragm was not different in acidotic and control animals. 7. 7. The addition of various substrates (valine, leucine and NH4Cl) stimulated glutamine production to similar extent in control and acidotic animals. 8. 8. While alanine was produced by the diaphragm of the normal animals, it did not occur in the acidotic rats. Furthermore the addition of substrates did not stimulate alanine production by the diaphragm of the acidotic animals. 9. 9. Addition of methionine sulfoximine (MSO) 5 mM to inhibit diaphragm glutamine synthetase activity resulted in a 55% decrease in glutamine synthesis in both normal and acidotic animals. 10. 10. The production of glutamine or alanine was not affected by acidification of the incubation medium from pH 7.4 to 7.0. 11. 11. Our findings suggest that the capacity for glutamine synthesis by the skeletal muscle is not affected by metabolic acidosis. 12. 12. The fall in glutamate and the rise in ammonia concentrations in the skeletal muscle in vivo during metabolic acidosis suggest that glutamate availability is rate-limiting for the production of glutamine. This could explain the marked variations in alanine metabolism. 13. 13. In view of the very small changes observed in glutamine production by the skeletal muscle during acidosis, the role of other tissues such as the liver, the brain and, in the rat, the kidney, should be envisaged. 14. 14. The possibility of a significant decrease in glutamine metabolism by the intestine during acidosis making more glutamine available for renal extraction should also be seriously considered.

Effect of Valproate on Lactate and Glutamine Metabolism by Rat Renal Cortical Tubules

Abstract The metabolic effects of sodium valproate (VPA) on rat renal cortical tubules have been examined. When 1 or 5 mM lactate was used as substrate in the incubation medium, VPA decreased markedly the lactate uptake by the tubules. When 1 or 5 mM glutamine was used, the addition of VPA accelerated glutamine uptake, ammoniagenesis, but also stimulated markedly the accumulation of lactate and pyruvate produced from glutamine. VPA had a dose-dependent inhibitory effect on gluconeogenesis from both glutamine and lactate. With 5 mM glutamine, VPA also induced a significant accumulation of glutamate in the medium. The oxygen consumption by the tubules was diminished by 40% following VPA addition. It is concluded that VPA modifies the metabolism of rat cortical tubules by interfering with the oxidation of natural substrates and stimulates in this fashion the production of ammonia by kidney tubules.

Response of the rat and dog kidney to H+ concentration in vitro—A comparative study with slices and tubules

Abstract 1. 1. The present study reevaluates the metabolic response of rat and dog renal cortical tissue to changes in H + concentration of incubation medium and compares the response of kidney slices to (hat of isolated tubules. 2. 2. In the rat, acidification (pH 7.1) depresses glutamate accumulation and enhances gluconeogenesis with both slices and tubules, but glutamine extraction and ammonia production increase significantly only with tubules. 3. 3. Alkalinization (pH 7.7) depresses glucose and ammonia production and enhances glutamate accumulation with both slices and tubules but glutamine extraction is also slightly stimulated with tubules only. 4. 4. Thus, in the rat, variations of incubation medium pH modulates (a) glutamate utilization and (b) glutamine transport from the medium to the mitochondria, the second effect being apparent with tubules only. The different response observed with slices and tubules is attributed to a difference of permeability for glutamine between these two preparations. 5. 5. The intracellular metabolite profile of tubules rapidly separated from the incubation medium after 30 min suggests that in vitro acidosis increases and alkalosis decreases glutamate utilization and ammonia production probably by affecting the activity of the alpha-ketoglutarate dehydrogenase complex. 6. 6. In the dog, no effect of H + concentration on glutamine transport or utilization can be seen. However, H + concentration modifies glutamate accumulation and stimulates gluconeogenesis (from glutamate and endogenous substrates). 7. 7. Both effects are in accord with observations in the rat and may involve similar mechanisms.

A Brush Border Membrane-Bound H+ -ATPase from the Dog Proximal Tubule

We have characterized the H+-ATPase activity (ATP hydrolysis and proton transport) of brush border membranes (BBMs) isolated from the dog kidney cortex. In solubilized BBMs, two thirds of t

Metabolie Effects in Man of Tienilic Acid, a New Diuretic with Uricosuric Properties

Acute and chronic studies were performed on 6 bealthy human volunteers. Four subjects took a Single oral dose of tienilic acid 1,000 mg. A week later, the same subjects took pyrazinamide (PZA) orally

Glucose Metabolism in Dog Inner Medullary Collecting Ducts

The adenosine triphosphate (ATP) generating pathways of dog inner medullary collecting ducts (IMCD) were examined in vitro using suspensions of dog IMCD tubules incubated under aerobic and anaerobic conditions. Glucose is always the preferred substrate for this tissue, even if lactate can be oxidized under aerobic conditions. The metabolism of glucose proceeds largely towards lactate accumulation in the presence or absence of oxygen. Glycogen is also consumed and more markedly so during anoxia. The pentose shunt represents a minor pathway for glucose metabolism in this tissue. Under aerobic conditions, the net oxidation of glucose to CO2 contributes significantly to the cell energetics, mitochondrial and cytoplasmic mechanisms sharing equally the ATP synthesis. In the absence of oxygen, only the cytoplasmic routes of ATP synthesis are used, but the apparent ATP turnover is markedly reduced. A marked inhibition of the activity of the Na-K-ATPase during anoxia explains this observation. The utilization of glucose for osmolyte synthesis is a minor process and appears to be suppressed under anaerobic conditions. It is concluded that the ATP turnover is low in dog IMCD cells as compared with that of other nephron segments and is largely dependent upon glucose availability under aerobic or anaerobic conditions.

Metabolism of tienilic acid (ticrynafen) in man. Pharmacokinetic and mass spectrometric studies

SummaryThe pharmacokinetics and metabolism of tienilic acid (ticrynafen) a new diuretic with uricosuric properties, were studied in human volunteers following single ingestion of 250, 500 or 1000 mg. Tienilic acid was found to be extentively (more than 98%) bound to plasma proteins but not to displace the fraction of urate bound to plasma proteins at the usual therapeutic dosage (250 to 500 mg). The uricosuric and natriuretic effects of the drug lasted 8 to 12 hours. A peak concentration of 2.5, 4.5 or 10.1 mg/dl was noted in the plasma 2 hours following ingestion of each dose. The apparent volume of distribution of the drug was close to that of plasma volume. Tienilic acid disappeared rapidly from the plasma according to a first order kinetics and the plasma half-life ranged from 1.6 to 2.4 hours. Gas chromatography and mass spectrometric studies revealed that 21% of the ingested tienilic acid is excreted as such in the urine over 24 hours. Three major metabolites of the drug were identified in the urine: a monohydroxylated, a dihydroxylated and a diacid product. Including metabolites, 36 to 47% of the drug was excreted in the urine within 24 hours. No significant glucuro or sulfoconjugation of the drug or its metabolites could be detected in the urine. Excretion of the drug and its metabolites was also noted in the bile. It is concluded that tienilic acid is rapidly metabolized and excreted in humans with normal kidney and liver function.

The Renal Handling of Tienilic Acid (Ticrynafen), a New Diuretic with Uricosuric Properties

Tienilic acid (ticrynafen) [2,3-dichloro-4-(2-thyenil-carbonyl) phenoxyacetic acid] is a new diuretic with uricosuric properties in man and dog. In this animal the drug acts by blocking tubular transp

Heterogeneous Metabolism and Toxicity of 4-Pentenoate along the Dog Nephron

4-Pentenoate (4P) is a short-chain fatty acid which causes a complete renal Fanconi syndrome. We have examined the mechanism of 4P toxicity along the nephron after a prolonged (30 min) exposition of isolated renal tubular segments to this agent. In proximal tubules, 4P inhibited the activity of alpha-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and beta-oxidation, but not in thick ascending limb or inner medullary collecting duct tubules in suspension. These proximal effects were accompanied by a marked oxidation of the proximal redox state, with a fall in the tissue respiration and a low content of ATP. The acetyl-CoA content of proximal tubules was simultaneously reduced. Butyrate, acetate, hexanoate or octanoate did not exert these effects. In proximal tubules the metabolism of 4P led to the tissue accumulation of 3-keto-4-pentenoyl-CoA, a known unspecific inhibitor of metabolic oxidation. This metabolite was not detectable in thick ascending limbs which metabolized 4P rapidly. No metabolism of 4P was noted in collecting ducts. We conclude that beta-oxidation probably differs in proximal and thick ascending limb tubules, allowing 4P metabolism to exert a specific toxicity in proximal tubules. A selective proximal defect in energy metabolism probably explains the Fanconi syndrome observed with exposition to 4P.