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PubMed2004

A simple, safe and effective citrate anticoagulation protocol for the genius dialysis system in acute renal failure.

BACKGROUND: The Genius dialysis system is a close loop dialysis batch system increasingly used as an intermittent hemodialysis device in intensive care units. The aim of this study was to test the safety and feasibility of a regional citrate anticoagulation protocol with respect to acid-base and electrolyte disarrangements in critically ill patients with acute renal failure. A standard heparin anticoagulation protocol served as control. METHODS AND RESULTS: In a cross-over study design, 27 acute renal failure patients were allocated to a citrate- and heparin-anticoagulated dialysis sessions (4-6 h). For citrate anticoagulation, a 4% sodium-citrate solution was infused into the arterial line of the extracorporeal circuit. A low calcium dialysate (1 mmol/l) was used for all dialysis sessions. Citrate dosing was adjusted according to the post-filter ionized calcium concentration (targeted values 0.5-0.7 mmol/l). There was no routine calcium substitution. Heparin anticoagulation was started with a heparin-loading dose followed by an individual, patient-adjusted continuous heparin infusion. Electrolyte disarrangements, namely hypernatremia, hypo- and hypercalcemia did not occur in either group. Although the highest bicarbonate levels were achieved during citrate anticoagulation (p = 0.021 versus heparin) the acid base values remained equilibrated in both groups. Filter longevity was excellent and the targeted dialysis time was achieved in all but 1 patient. Citrate anticoagulation was well tolerated with respect to cardiovascular hemodynamics. CONCLUSIONS: Citrate anticoagulation can be safely and effectively performed during intermittent Genius dialysis. Calcium supplementation is not routinely required.

Acid-Base Equilibrium↗
PubMed1991

Renal handling of citrate in chronic renal insufficiency.

Citrate is a relevant component of the inhibitory potential of the urine environment. Its excretion and renal handling have been widely studied in subjects with normal renal function, but little is known about changes induced by chronic renal insufficiency. We have investigated renal handling of citrate in 50 patients with different degrees of renal insufficiency as compared to 30 healthy subjects with normal renal function. Among patients 34 were defined as having mild renal insufficiency based on a GFR of 80 through 40 ml/min/1.73 m2 BSA, while 16 had moderate-to-severe renal failure, defined by a GFR ranging from 40 to 20 ml/min/1.73 m2 BSA. Serum citrate increased in mild renal insufficiency, while it tended to be restored to normal values at more advanced renal failure. There was a stepwise decrease in the filtered load of citrate as GFR decreased, while its renal clearance was significantly reduced only at higher degrees of renal failure. This behavior was due to an increase in the fractional excretion of citrate which was inversely related to the decrease in GFR (p = 0.015). These data suggest that serum citrate levels and excretion are governed by renal mechanisms at mild degrees of renal insufficiency; in these conditions citrate is shown to behave conformly to other poorly reabsorbable anions such as sulfate. At more advanced renal failure the ensuing metabolic acidosis plays a crucial role as a regulatory factor of both serum concentration and renal handling of citrate, by increasing cellular uptake and metabolism as well as tubular reabsorption of this anion.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Imbalance↗
PubMed1981

Studies on pancreatic stones. II. Citrate secretion in the canine pancreatic juice.

In a previous study, we found that pancreatic stones could be dissolved in vitro by a citrate solution. We then decided to look for the possible secretion of citrate into the pancreatic juice, and to find a means of increasing it. Pancreatic juice secretion was collected in Thomas fistula dogs submitted to four protocols: basal conditions, secretin stimulation (0.5 and 2.0 U . kg-1 . h-1), caerulein boluses (25 and 100 ng . kg-1) superimposed on 0.5 U . kg-1 . h-1 secretion and intraduodenal citrate infusion (1.05 mmol . kg-1 . h-1). Under basal conditions mean citrate output per 15 min was 0.11 +/- 0.02 mumol. During secretin and caerulein stimulation, citrate output paralleled that of protein, and a linear regression was calculated: Ycitrate = -0.013 + 0.019 Xprotein (mumol/mg). Intraduodenal citrate infusion induced a sharp increase in citrate output which reached 11.5 mumol/15 min, but only 0.12% of the infused citrate amount was secreted into pancreatic juice during 1 h.

Animals↗
PubMed1976

A study of the permeability of the guinea pig placenta to citrate using recirculating placental perfusion technique.

The role of the guinea pig placenta in fetal citrate metabolism has been studied by perfusing the placenta in situ. The initial citrate concentrations in the perfusate plasma were lower than in the maternal plasma but rose progressively until, in some cases, they exceeded those in the mother. The rise was uninfluenced by intravenous administration of citrate to the mother. Citrate therefore does not enter the perfusate by simple diffusion from the maternal compartment. It may be synthesised within the placenta. From the rate of accumulation of citrate in the perfusate, the supply to the fetus was calculated to be small compared to the fetal metabolic rate. Citrate added to the perfusate became distributed in a space similar to the extracellular space and no change occurred in maternal citrate concentrations. Thus, the placenta does not appear to metabolise citrate or allow transport to the mother.

Animals↗
PubMed1995

Renal excretion of aluminium in the rat: effect of citrate infusion.

When aluminium is administered intravenously to rats, the speciation of the aluminium has a major effect on its renal excretion. Aluminium administered as citrate is much more effectively excreted than that administered as chloride or sulphate. This suggests that citrate could be therapeutically useful in patients who have been exposed to aluminium. Accordingly, we have performed two series of experiments in rats, in which a citrate infusion (intravenous), was begun either immediately after, or one hour after, the administration of an intravenous aluminium sulphate bolus. Both protocols led to markedly enhanced aluminium excretion compared to controls in which only 0.7% NaCl was infused. The enhancement of aluminium excretion was 783% if citrate infusion was begun immediately after aluminium administration, and 335% if the citrate infusion began after an hour delay. The increased excretion was due to an increase in the freely filterable fraction of aluminium. In the control experiments, in which aluminium sulphate administration was followed by 0.7% NaCl infusion, aluminium was found to be deposited in the liver. Administration of citrate one hour after the aluminium bolus did not reduce this liver deposition. The results indicate that a fraction of the plasma aluminium is accessible to the citrate infused and can thereby be converted into a filterable form which can be excreted. It appears that, for maximum therapeutic effect, citrate should be infused as rapidly as possible after an aluminium load, to limit aluminium binding to ligands which allow it to enter cells.

Alum Compounds↗
PubMed2000

Caffeine citrate for the treatment of apnea of prematurity: a double-blind, placebo-controlled study.

STUDY OBJECTIVE: To evaluate the efficacy and safety of caffeine citrate for treatment of apnea of prematurity. DESIGN: Multicenter, parallel, randomized, double-blind, placebo-controlled trial with open-label rescue. SETTING: Nine neonatal intensive care units. PATIENTS: Eighty-five infants, 28-32 weeks postconception and 24 hours or more after birth who had six or more apnea episodes within 24 hours. INTERVENTION: Caffeine citrate 10 mg/kg (as caffeine base) administered intravenously, followed by 2.5 mg/kg/day orally or intravenously, or placebo, for up to 10 days. Infants failing double-blind therapy could receive open-label rescue. MEASUREMENTS AND MAIN RESULTS: Success was defined as 50% or greater reduction in apnea episodes and elimination of apnea. Caffeine citrate was significantly more effective than placebo in reducing apnea episodes by at least 50% in 6 days (p<0.05), and approached statistical significance (p<0.10) in 3 days. It was significantly better than placebo in eliminating apnea in 5 days (p<0.05), and approached significance (p<0.10) in 2 days. The number of infants with an aggregate of 7-10 days of at least a 50% reduction in apnea events or elimination of apnea was significantly higher in the caffeine citrate than in the placebo group. Adverse events did not differ significantly between groups. No correlations were found between success and mean daily plasma concentrations or baseline characteristics. Volume of distribution and clearance increased with weight, supporting weight-adjusted dosing of caffeine citrate. CONCLUSION: Caffeine citrate 10 mg/kg caffeine base (equivalent to 20 mg/kg caffeine citrate) intravenously followed by 2.5 mg/kg/day caffeine base (equivalent to 5 mg/kg/day caffeine citrate) either intravenously or orally for 10 days is safe and effective for treating apnea of prematurity in infants 28-32 weeks postconception.

Apnea↗
PubMed1987

Endocrine changes and urinary citrate excretion.

Urinary citrate affects the ion-activity products of calcium oxalate and calcium phosphate and inhibits the growth of these crystals. Women are less prone to develop calcium stones and because they also excrete more citrate than men, an effect of sex steroids on citrate excretion might be important. We therefore analysed urinary citrate and creatinine before and during treatment with estrogen alone or together with medroxyprogesterone acetate in 29 postmenopausal women and at different gestational ages in 19 pregnant women. Urinary citrate and creatinine was also determined before and after orchidectomy in ten men with carcinoma of the prostate. The excretion of citrate and the ratios between citrate and creatinine were not significantly altered by pregnancy or orchidectomy. Neither did treatment with estrogen or estrogen/medroxyprogesterone acetate affect these variables. We were unable to explain the difference in citrate excretion between men and women by effects of sex steroids.

Adult↗
PubMed1992

Urinary excretion of citrate, glycosaminoglycans, magnesium and zinc in relation to age and sex in normal subjects and in patients who form calcium stones.

One hundred and ninety-seven healthy subjects and 104 patients with idiopathic calcium stone disease had their urinary excretion of citrate, glycosaminoglycans, magnesium, and zinc measured and the results correlated with sex and age. In normal subjects the daily excretion of citrate, magnesium, and zinc increased with age to a maximum during the fifth decade and remained relatively constant until the eighth decade when they decreased. The daily excretion of magnesium and zinc were higher in men than in women, which was attributed to the higher body weights of the men. The urinary excretion of citrate, magnesium, and zinc related to creatinine remained relatively constant with age in adult life; analyses of magnesium and zinc excretion rates divided by urine creatinine did not distinguish men from women. There was no significant difference between men and women for citrate excretion in 24 hour urine, but the citrate:creatinine ratio was significantly higher in women than men. The higher citrate excretion in women may explain the lower incidence of calcium stones in women. The highest glycosaminoglycan excretion rates were seen during the first two decades which is why children and teenagers are less prone to develop calcium stones in spite of high urinary calcium concentrations. Urinary citrate and magnesium excretion were lower, and glycosaminoglycan and zinc excretion were higher, in stone formers than in controls. It seems that a decreased excretion of citrate and magnesium together with an increased excretion of calcium, may contribute to the formation of calcium stones. The role of urinary glycosaminoglycans and zinc in the formation of calcium stones remains uncertain.

Adolescent↗
PubMed1982

Indirect androgenic control of citrate accumulation in rat ventral prostate.

Androgenic control of citrate metabolism was studied by measuring the conversion of (2-14C)acetate or (6-14C)glucose to (14C)citrate and 14CO2 in the ventral prostate of the rat. The decarboxylation of (2-14C)acetate showed that androgen preferentially increased (14C)citrate oxidation, probably to meet the increased energy demands of cellular synthetic reactions. This led to the decreased accumulation of (14C)citrate from (2-14C)acetate. On the other hand, both the production of (14C)citrate and the formation of 14CO2 from (6-14C)glucose were decreased by castration and increased by testosterone, this being mainly due to the androgenic control of pyruvate dehydrogenase. These changes were more marked and rapid than those in oxygen consumption, in (2-14C)acetate oxidation, or in the total content of prostatic citrate that was maintained by testosterone. Glucose as the main source of citrate in testosterone-treated rats can thus be replaced by alternative substrates in castrated rats. The rate of citrate accumulation could be more dependent on the number of secretory cells than their hormonal activation.

Acetates↗
PubMed2000

[Cloning and tissue expression pattern analysis of the human citrate synthase cDNA].

Tricarboxylic acid (TCA) cycle is an important way to generate ATP, which is widely distributed in the cells of animal, plant or microorganism. It catalyses the catabolism of sugar as well as protein and fat. Citrate synthase plays a key role in regulating TCA cycle and is responsible for catalysing the synthesis of citrate from oxaloacetate and acetyl CoA. Screening of genomic informatics was performed by using pig citrate synthase cDNA as a probe and a contig which is 1636 bp long and has highly homologous to the pig citrate synthase cDNA was obtained from selected ESTs with the ASSEMBLY program. According to the sequence of this contig, a pair of primers was designed and used to amplify cDNA libraries. A 1492 bp cDNA containing an open reading frame encoding 466 amino acids was cloned from human testis and skeletal muscle cDNA libraries. The deduced amino acid sequence of the cDNA showed 95%, 92% and 60.9% identity to pig, chicken and yeast citrate synthase respectively. Because the deduced amino acids sequence contains a highly conserved motif of citrate synthase from three different species, it is believed that this cDNA may be a transcript of human citrate synthase gene. Northern analysis showed that the human citrate synthase was expressed at high level in heart and muscle, at middle level in brain, kidney and pancreas tissues, not detectable in thymus and small intestine tissues, and at low level in other nine tested human tissues.

Amino Acid Sequence↗
PubMedDate not supplied

[Effect of glucose and lactose on the utilization of citrate by Lactobacillus casei subsp. rhamnosus ATCC 7469].

The utilization of citrate by Lactobacillus casei subsp. rhamnosus ATCC 7469 in a complex medium containing glucose, lactose or citrate was investigated, as an approach to the question of the transport of this acid and the possible relationship with the production of flavour compounds (diacetyl and acetoin). This lactobacillus uses citrate as an energy source in the absence of carbohydrates. External pH and growth increases when citrate is added to complex medium. The presence of citrate does not affect glucose uptake. L. casei ATCC 7469 possibly uses a transport system for citrate utilization, and citrate uptake seems to be under glucose or lactose control. Lactose only inhibits the entrance of citrate at high concentration while the utilization of this acid was negatively regulated by low glucose concentration.

Biological Transport↗
PubMed1992

[Clinical study of Urocit-K: a slow releasing potassium citrate].

Citrate is recognized as one of the inhibitors of urinary stone formation. If the urinary citrate and pH could be elevated by the supply of potassium citrate, the recurrence of stone formation would hopefully be prevented. Urocit-K is a kind of slow releasing preparation of potassium citrate. The pharmacokinetics of Urocit-K is investigated in this study, which included two groups: 1) the hypocitraturia group consisting of twenty patients and 2) the normal volunteer group consisting of ten persons. Urokit-K was administered to patients in 10 mEq doses, t.i.d. for 2 weeks. Comparison of urinary biochemistry was done prior to, and one week after administration of the Urocit-K. In the normal volunteer group, the pharmacokinetics of Urocit-K was determined by urinary pH, K, and citrate. Determinations were made six times a day (every 2-hours for first 8 hours, 7- and 9- hours for the last 16 hours) with Urocit-K for comparison. This study indicated that Urocit-K increases urinary pH, K, and citrate in hypocitraturic patients. In the normal volunteer group, Urocit-K deserves its slow-releasing property shown by a constant increase of urinary pH and K for the first 8 hours; and urinary citrate for almost 24 hours. No apparent complications, such as gastrointestinal upset or cardiopulmonary discomfort were observed. In conclusion, Urocit-K is an excellent preparation of potassium citrate and a good choice for prevention of stone recurrence.

Citrates↗
PubMed1990

Topical citrate inhibits the adherence of neutrophils to postcapillary venules.

The high incidence of corneal ulceration in the alkali-injured rabbit eye can be reduced by topical citrate drops. Citrate interferes with polymorphonuclear leukocyte (PMN) accumulation in the corneal stroma after alkali injury. It inhibits the adherence, locomotion, respiratory burst, phagocytosis, and degranulation of human PMNs in vitro. The objective of this research was to determine if PMN adherence to the vascular endothelium could be inhibited by superfused citrate in vivo. PMN adherence to the endothelium of postcapillary venules in the hamster cheek pouch was greatly enhanced and maintained by addition of leukotriene B4 (LTB4) to the superfusate. Superfusion of the pouch with 24 mM citrate for 5 min, before addition of LTB4, inhibited PMN adherence to the endothelium. The free calcium level in the superfusate was reduced from approximately 650 to 33 microM in the presence of 24 mM citrate. When LTB4-augmented PMN adherence was allowed to occur, followed by citrate treatment (24 mM), it was reversed. Simultaneous addition of CaCl2 and MgCl2 to the superfusate raised the free Ca2+ level to 786 microM and reversed the citrate-induced inhibition of LTB4-augmented adherence. From this and other research, we conclude that citrate probably inhibits adherence of PMNs to pericorneal and conjunctival vessels in the eye, preventing their accumulation in the corneal stroma.

Administration, Topical↗
PubMed1990

Alkaline citrate in prevention of recurrent calcium oxalate stones.

Calcium oxalate (CaOx) is the most common constituent of calcium renal stones, often mixed with calcium phosphate (CaP). The recurrence rate of these stones is high and their aetiology complex. Despite new effective, less invasive methods to remove the stones, preventive treatment is often necessary to avoid recurrence. Alkaline citrate is a relatively new medical treatment reported to give a stone free rate of between 67-92 per cent in long term studies with three daily doses. The present investigation was undertaken in order to study further the risk factors in CaOx stone formation, the influence and usefulness of a single evening dose of alkaline citrate, and the value of a four hour morning urine sample in the evaluation of patients who form stones. The highest CaOx crystallisation risk (CaOx-CR) in whole urine was recorded in the pH range 4.5-5.5, with lower values above this pH. Between pH 6.5-7.5 the number of small CaP crystals was considerably increased. The crystallisation of CaOx on hydroxyapatite (HAP) was inhibited for four hours by 1 and 2% whole urine or citrate in concentrations of 1% that in normal urine. The formation of CaP crystals in a supersaturated system was considerably reduced when citrate concentrations exceeded 0.5 mmol/l. The number of medium sized (6.5-14 microns) and large crystals (15.5-27 microns) was reduced, and small crystals (3.5-5 microns) predominated at higher citrate concentrations. The correlation between the composition of 24-h urine samples and 4-h urine specimens collected between 0600-1000, from patients with CaOx stones before and during a course of alkaline citrate given as a single evening dose was good, with the best correlation recorded during treatment. These results suggest that the 4-h urine sample might be adequate for the follow up of patients treated with alkaline citrate. A total amount of 7.5 g of potassium sodium citrate (PSC) in 1, 2, and 3 doses favourably affected urine composition in patients with CaOx stones. Three doses gave the most sustained effect, and a single evening dose gave the most pronounced effect between 2200-0600. Long term treatment (mean +/- SD duration 3.5 +/- 1.7 years) of patients who formed calcium stones with PSC in a single evening dose of 3.75 or 5.0 g (n = 55) gave a stone free rate of 75 per cent, but no clinical effect was apparent when 5.0 or 7.5 g were given in two or three doses (n = 17).(ABSTRACT TRUNCATED AT 400 WORDS)

Antacids↗
PubMedDate not supplied

[Citrate transport in submitochondrial particles of the rat liver].

The submitochondrial particles (SMP, inverted inner membrane vesicles of mitochondria of the turned out vesicles in internal mitochondrial membranes) of the rat liver are characterized for their ability to incorporate [14C]citrate depending on the concentration of exogenic citrate, temperature and time of incubation. The rate of citrate incorporation into SMP does not depend on the addition of the oxidation substrate into the medium, however in the presence of malate and phosphate it is sharply activated. 1,2,3-benzene tricarboxylase (1,2,3-BTC) is an active inhibitor of the citrate transport into SMP. The citrate transport is determined by the protonation-deprotonation processes of the carrier protein on the outer and inner side of the membrane. A decrease in the pH of the medium favours protonation of the carrier protein on the outer side of the membrane and intensifies [14C]citrate incorporation into SMP, whereas the pH increase inhibits this process. The effect of pH changes is less pronounced in the presence of K+ ions. Valinomycin in the K+ medium activates incorporation of [14C]citrate increasing the carrier protein deprotonation rate on the inner side of the SMP membrane. Protonophore separators intensify conductivity for H+ ions and remove the stimulating influence of valinomycin on the rate of [14C]citrate incorporation into SMP.

Animals↗
PubMed1985

The effect of sodium citrate on the stimulation of polymorphonuclear leukocytes.

Topical administration of sodium citrate reduces the incidence of corneal ulceration and perforation following an alkali burn to the eye. The specific mechanism by which sodium citrate prevents the ulceration is not understood, although citrate does inhibit the infiltration of polymorphonuclear leukocytes (PMNs) into the cornea following an alkali burn. In the present study, the effects of sodium citrate and another calcium chelator, ethylene glycol bis (beta-aminoethylether)-N,N'tetraacetic acid (EGTA), upon PMN oxygen consumption and lysosomal enzyme release were determined. Oxygen consumption was measured polarographically using a Clark-type oxygen electrode, and lysosomal enzyme release was determined by intra- and extra-cellular measurements of myeloperoxidase activity. Opsonized zymosan and N-formylmethionylleucylphenylalanine (FMLP) were used to stimulate neutrophil oxygen consumption and lysosomal release. Both sodium citrate and EGTA inhibited PMN oxygen consumption and lysosomal enzyme release in response to opsonized zymosan. In contrast, neither sodium citrate nor EGTA reduced PMN oxygen consumption or lysosomal enzyme release in response to FMLP. Therefore, the ability of sodium citrate (and EGTA) to inhibit PMN stimulation is dependent upon the choice of stimulus. Until the inflammatory mediators involved in the ulcerative process following an alkali burn to the eye are delineated, the impact of sodium citrate upon PMN stimulation in vivo cannot be resolved.

Burns, Chemical↗
PubMed1986

Subunit equilibria of porcine heart citrate synthase. Effects of enzyme concentration, pH, and substrates.

Porcine heart citrate synthase, a dimeric protein of Mr = 100,000 composed of two identical subunits, is shown to undergo a monomer-dimer equilibrium. The extent of dimerization is found to be dependent on the concentration of citrate synthase, pH, ionic strength, and the specific buffer system employed. Oxaloacetate and citrate, substrates for the forward and reverse reaction catalyzed by citrate synthase, affect dimerization at concentrations of the protein which exists as monomer in their absence. The dissociation of citrate synthase dimers has been demonstrated utilizing the techniques of gel permeation chromatography, fluorescence polarization, fluorescence energy transfer, and heat denaturation. Earlier studies of citrate synthase quarternary structure found the protein to be nondissociable except under denaturing conditions or extensive modification; however, most former studies were performed at relatively high protein concentration, ionic strength, and pH, conditions which stabilize the dimer. In light of recent evidence derived from x-ray crystallographic studies showing amino acid residues from one subunit contributing to the citrate and CoA binding sites of the other, the dissociation into monomers would be expected to have profound effects on citrate synthase activity and regulation, as well as overall tricarboxylic acid cycle activity.

Animals↗
PubMed1985

Urinary citrate excretion in normal persons and patients with idiopathic calcium urolithiasis.

The 24-hour urinary excretion of citrate was measured in 83 normal persons and in 132 consecutive patients with idiopathic calcium urolithiasis, uninfected urine, and normal renal function. The urinary excretion of citrate in normal men was not significantly different from that in normal women (P greater than 0.05). There was a significant (P less than 0.001) increase of urinary citrate excretion with increasing age in normal persons. No increase of urinary citrate excretion with age was demonstrated in stone formers. There was no statistically significant difference between active and inactive stone formers in regard to regression of the citrate/calcium ratio or the citrate/uric acid ratio, and there was no difference in these ratios between men and women considered separately or in subgroups by hypercalciuria or hyperuricuria or by individual age. Hypocitraturia was found in 29.2% of patients with idiopathic calcium urolithiasis. No relationship could be demonstrated between the 24-hour urinary excretion of citrate and severity of stone disease before presentation at our clinic or the frequency of stone growth or new stone formation at follow-up. Twenty-two of 35 patients with hypocitraturia had multiple urinary citrate measurements. In 15 of these 22 patients, at least one normal urinary citrate measurement was obtained. Further prospective study is required to establish the value of urinary citrate determinations in patients consuming an uncontrolled diet in an outpatient setting.

Adult↗