Urinary Citrate Excretion Research Articles

Citraturic Response to Oral Citric Acid Load

It is possible that some orally administered citrate may appear in urine by escaping oxidation in vivo. To determine whether this mechanism contributes to the citraturic response to potassium citrate, we measured serum and urinary citrate for 4hours after a single oral load of citric acid (40 mEq.) in 6 normal subjects. Since citric acid does not alter acid-base balance, the effect of absorbed citrate could be isolated from that of alkali load. Serum citrate concentration increased significantly (p <0.05) 30 minutes after a single oral dose of citric acid and remained significantly elevated for 3hours after citric acid load. Commensurate with this change, urinary citrate excretion peaked at 2hours and gradually decreased during the next 2hours after citric acid load. In contrast, serum and urinary citrate remained unaltered following the control load (no drug). Differences of the citratemic and citraturic effects between phases were significant (p <0.05) at 2 and 3hours.Urinary pH, carbon dioxide pressure, bicarbonate, total carbon dioxide and ammonium did not change at any time after citric acid load, and did not differ between the 2 phases. No significant difference was noted in serum electrolytes, arterialized venous pH and carbon dioxide pressure at any time after citric acid load and between the 2 phases. Thus, the citraturic and citratemic effects of oral citric acid are largely accountable by provision of absorbed citrate, which has escaped in vivo degradation.

Urinary Acidification in Renal Stone Patients from Northeastern Thailand

Hypokalemia, hypokaliuria and hypocitraturia are common findings in patients with renal stone disease in Northeastern Thailand. However, hyperchloremic metabolic acidosis seldom is seen. Therefore, we studied renal acidification in 29 renal stone disease patients who were living in rural Northeast Thailand. Baseline blood and average 24-hour urine biochemical parameters were measured. Hypokalemia, hypokaliuria and hypocitraturia were found in 10%, 83% and 93% of the patients, respectively. By multiple regression, urinary citrate excretion correlated positively with serum potassium and urinary potassium excretion, and negatively with urinary ammonium (r = 0.640, p = 0.005). An abnormal response to acid loading was found in only 1 patient. Thus, hypokaliuria and hypocitraturia in our renal stone disease subjects were infrequently due to distal renal tubular acidosis. Perhaps potassium depletion might be a contributing factor in these metabolic abnormalities.

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.

Urine metabolite values in fed and nonfed clinically normal Beagles

SUMMARY Twenty-four-hour excretion of urine metabolites was determined in 33 clinically normal Beagles during periods of consumption of a standard diet and when food was withheld. The goal was to determine normal canine values for urine analytes incriminated in the genesis of calcium oxalate uroliths. During periods when dogs consumed food, dairy urinary excretion of calcium, uric acid, sodium, potassium, magnesium, ammonium, and hydrogen ions were significantly (P = 0.0004, 0.0038, 0.001, 0.0001, 0.0004, 0.0001, and 0.024, respectively) higher than when food was withheld. Urinary excretion of phosphorus, oxalate, and citrate were not significantly different between samples obtained during periods of food consumption and when food was withheld. Male dogs excreted significantly higher quantities of urine oxalate than females during fed (P = 0.003) and nonfed (P = 0.003) conditions. When food was withheld, urinary uric acid excretion was significantly higher in males than females (P = 0.01). Females excreted significantly more urine calcium than males when food was withheld (P = 0.003). Our results indicated that dietary conditions influence the quantity of sodium, potassium, calcium, magnesium, and uric acid excreted in the urine of clinically normal dogs; therefore, dietary conditions should be considered when measuring the concentration of these analytes in urine.

In vivo and in vitro rat model for cyclosporine-induced proximal tubular toxicity.

Cyclosporine is used widely to prevent transplant rejection. Unfortunately, this drug causes both renal glomerular and tubular damage. To develop a stable reproducible noncatabolic animal model of cyclosporine nephrotoxicity, rats were fed a special liquid diet and daily administered 7.5 mg/kg of cyclosporine intramuscularly. Twenty-one days after this regimen was started, the body weight of cyclosporine-treated rats had increased 15%, a value only 38% less than the increase in pair-fed controls. After 21 days, glomerular filtration rate fell 34% in cyclosporine-treated rats (p less than 0.001) compared with the pair-fed controls. Simultaneously, citrate and N-acetylglucosaminidase excretion increased significantly. When isolated proximal tubules obtained after 21 days from the cyclosporine and pair-fed rats were incubated by using 1.0 mmol/L glutamine and 1.0 mmol/L citrate substrates, ammonia production was reduced 40% and glucose production reduced 20% (p less than 0.001) in the cyclosporine-treated rats. Discontinuing cyclosporine for 7 days partially reversed all these changes. The glomerular filtration rate in cyclosporine-treated rats now was only 15% below that in controls (p less than 0.05), N-acetylglucosaminidase excretion was the same in both groups, and urinary citrate excretion in the cyclosporine-treated rats fell from 122% to 62% above that in controls. In vitro differences in tubular ammonia and glucose production also narrowed. In summary, these experiments describe a stable reproducible noncatabolic and at least partially reversible rat model for studying cyclosporine nephrotoxicity.

Chronobiology of urinary citrate excretion amongst stone-formers and healthy males from North Western India

Urinary citrate excretion was estimated colorimetrically from urine samples collected every 3 h for 24 h from 25 healthy adult males (non-stone formers; mean age 39 +/- 7 years) and 25 male patients suffering from calcium nephrolithiasis (stone formers; mean age 41 +/- 6 years). The 24 h citrate excretion was 2.47 +/- 0.65 mmol in non-stone formers and 2.02 +/- 0.71 mmol in stone formers. This difference was not significant. However, cosinor rhythmometry revealed a significant circadian rhythmicity in urinary citrate excretion in the healthy males which was absent in the stone formers; the amplitude was 0.06 mmol in non-stone formers and 0.017 mmol in stone formers. The acrophase was located at 14:25 h in non-stone formers and at 23:30 h in stone formers.

Effect of Magnesium on Calcium Oxalate Urolithiasis

Previous studies have shown that hypomagnesuria induced by magnesium deficient diet causes calcium oxalate crystal deposition in renal tubules of hyperoxaluric rats and administration of magnesium to these rats results in prevention of calcium oxalate crystallization in their kidneys. Based on these studies magnesium was claimed to be beneficial for calcium oxalate stone patients. However, hypomagnesuria is not a common phenomenon. To better understand the role of magnesium as an inhibitor of calcium oxalate crystallization in urine, we studied the effect of magnesium on calcium oxalate urolithiasis in rats on a regular diet and a hyperoxaluric protocol. Excess magnesium was administered to male rats on regular diet and a lithogenic protocol. Magnesium administration to hyperoxaluric rats did not result in significant changes in urinary excretion of calcium or oxalate or in calcium oxalate relative supersaturation. Urinary excretion of citrate was also not significantly altered. Some animals from both groups, those on magnesium therapy and those not on magnesium therapy had crystals deposited in their renal tubules. We conclude that excess magnesium has no significant effect on calcium oxalate urolithiasis in normomagnesuric conditions.

Urinary excretion of nitrogenous and non-nitrogenous compounds in the chronic ethanol-fed rat

1. The metabolic consequences of chronic ethanol feeding was investigated by assay of urinary metabolites. Male Wistar rats were fed a liquid diet containing 35% of total energy as ethanol or isovolumetric, isocaloric and isonitrogenous amounts of the same diet in which ethanol was substituted by isocaloric glucose (controls). 2. At 6 weeks the entire skeletal muscle mass was reduced by approximately 20%. The urinary excretion of nitrogen, urea and uric acid increased by between 23 and 128%. Urinary creatinine excretion was not significantly altered. 3. Urinary excretion of magnesium was significantly increased by 43%. Urinary excretion of sodium, potassium, calcium and phosphate was increased slightly (i.e. 5-22%), but this change was not statistically significant. 4. Proton n.m.r. spectroscopic analysis showed that ethanol feeding reduced the urinary excretion of citrate and 2-oxoglutarate (by approximately 50%), suggesting decreased citric acid cycle activity. There was an increased excretion of alanine (44%), but excretion of succinate and acetate was not significantly altered. Ethanol in the urine of ethanol-fed rats comprised approximately 2% of total ethanol intake and less than 1% of total energy intake. 5. Lactose was detectable in urine of ethanol-fed rats, but not in control rats, reflecting the reported decreased intestinal lactase activity and increased gut permeability in alcoholics. Urinary galactose excretion decreased by 41%, but relatively large increases in lactate excretion (50%) did not achieve statistical significance. 6. It was concluded that chronic ethanol feeding causes disturbances in whole-body nitrogen homoeostasis and alterations in intermediary metabolism.

The Influence of Diet on Urinary Risk Factors for Stones in Healthy Subjects and Idiopathic Renal Calcium Stone Formers

The daily intake of 103 recurrent idiopathic calcium stone formers and 146 controls was assessed by means of a computer-assisted 24-h dietary record. Timed 24-h urine samples were collected over the same period to assess the relationship between dietary intake of nutrients and urinary risk factors for calcium stones. After standardisation for sex, age and social status a total of 128 subjects underwent final statistical analysis; 64 renal stone formers and 64 controls. Significant increases in the consumption of animal and vegetable protein and purine were identified as the nutritional factors that distinguished renal stone formers from controls. As expected, the daily urinary excretion of calcium and oxalate was higher and the daily urinary excretion of citrate was lower in stone formers than in controls. No difference with respect to daily urinary uric acid excretion was recorded. Daily urinary excretion of calcium was correlated to dietary protein intake while daily urinary oxalate was correlated to dietary vitamin C intake. It was concluded that renal stone formers could be predisposed to stones because of their dietary patterns. A link between the protein content of the diet and urinary calcium was confirmed, but dietary animal protein had a minimal effect on oxalate excretion.

Blood and Urinary Aggregator and Inhibitor Composition in Controls and Renal-Stone Patients from Northeastern Thailand

Renal-stone disease (RSD) is common in the rural communities of northeastern Thailand. We report the biochemical composition of blood and urine in 25 healthy city dwellers (G1), 12 healthy village dwellers (G2) and 25 village dwellers who had RSD (G3). They were male with a range of ages between 20 and 50 years and were free of renal failure, urinary infection, urinary obstruction and systemic illness. The results showed that hypocitraturia, hypokalemia and hypokaliuria were more common in the latter 2 groups. The 24-h urinary citrate excretion correlated significantly with urinary potassium in G3 cases (r = 0.704, p = 0.0002). After potassium chloride supplementation, serum and urinary potassium increased remarkably (p less than 0.003 and p = 0.002, respectively), whereas urinary citrate remained unchanged. Our results suggest that the predominant abnormality in our RSD patients were hypocitraturia and potassium deficiency and that these may be related.

Value of Routine Citrate Analysis and Calcium/Citrate Ratio in Calcium Urolithiasis

24-hour urinary citrate excretion was measured in 176 calcium oxalate stone formers and 100 normal controls. A statistically significant difference (p less than 0.03) could be found between the two groups. When stone formers were divided into a group of 69 patients with recurrent calcium urolithiasis (RCU) and a group of 106 patients with a single stone episode, the latter did not differ from the control group, while in RCU a significantly lower citrate excretion compared with controls (p less than 0.005) could be found. Thus, patients with RCU could benefit from alkali citrate prophylaxis. A female-male difference in citrate excretion could not be found in either the control group or stone formers. Recurrent stone formers presented a significantly higher calcium/citrate ratio compared with controls, which would indicate an increased risk for stone formation. The value of routine citrate analysis is limited, however, by the great, variability of citrate levels in stone formers and controls.

Renal handling of citrate

Intracellular citrate is a central component of the tricarboxylic acid cycle; its excretion in the urine was utilized by Krebs and coworkers to demonstrate this biochemical pathway in whole animals. Subsequently, urinary citrate has been viewed as a window on renal metabolism [1]. Additionally, renal physiologists and biochemists have been intrigued for decades by the dramatic changes in urinary citrate which occur with changes in acid-base homeostasis. In recent years, renal handling of citrate and citrate excretion in the urine have attracted renewed interest because of several considerations. First, modern techniques in renal physiology (such as, transport studies in brush border membrane vesicles and perfused proximal tubules) have provided insights into the cellular and molecular mechanisms of citrate transport [2]. Also, excretion of urinary citrate (and other organic anions) has been recognized to influence systemic acid-base status, at least in certain species [3]. And perhaps most importantly, urinary citrate has been increasingly recognized as an important endogenous inhibitor of calcium nephrolithiasis [4]. This review will focus on the renal handling of citrate, particularly the mechanisms of citrate transport in the proximal tubule, and briefly discuss other aspects of citrate metabolism.

Hyperoxaluria or hypercalciuria in nephrolithiasis: the importance of renal tubular functions

Abstract. The role of the kidney in states of hyperoxaluria and hypercalciuria was investigated in seven patients with hyperoxaluria after jejunoileal bypass (JIB) and six patients with idiopathic hypercalciuria (IHC). Eight apparently healthy persons formed a control group.Besides hyperoxaluria, the patients with JIB displayed an elevated plasma concentration of oxalate and the oxalate clearance was increased and higher than creatinine clearance, indicating a net tubular secretion of oxalate. The JIB patients had lower 24‐h urinary excretions of calcium, phosphate, magnesium and citrate and higher serum parathyroid hormone (PTH) than controls, indicating increased secretion of PTH to compensate for calcium malabsorption.IHC patients exhibited increased fasting urinary calcium even though their serum values were similar to those in the controls. These results indicate a reduced tubular calcium reabsorption, which was most pronounced in patients with highest PTH values.We conclude that hyperoxaluria in JIB patients is associated both with intestinal hyperabsorption and with enhanced tubular secretion of oxalate, and that in some patients with IHC hypercalciuria is due to reduced tubular reabsorption of calcium.

Hyperoxaluria or hypercalciuria in nephrolithiasis: the importance of renal tubular functions

The role of the kidney in states of hyperoxaluria and hypercalciuria was investigated in seven patients with hyperoxaluria after jejunoileal bypass (JIB) and six patients with idiopathic hypercalciuria (IHC). Eight apparently healthy persons formed a control group. Besides hyperoxaluria, the patients with JIB displayed an elevated plasma concentration of oxalate and the oxalate clearance was increased and higher than creatinine clearance, indicating a net tubular secretion of oxalate. The JIB patients had lower 24-h urinary excretions of calcium, phosphate, magnesium and citrate and higher serum parathyroid hormone (PTH) than controls, indicating increased secretion of PTH to compensate for calcium malabsorption. IHC patients exhibited increased fasting urinary calcium even though their serum values were similar to those in the controls. These results indicate a reduced tubular calcium reabsorption, which was most pronounced in patients with highest PTH values. We conclude that hyperoxaluria in JIB patients is associated both with intestinal hyperabsorption and with enhanced tubular secretion of oxalate, and that in some patients with IHC hypercalciuria is due to reduced tubular reabsorption of calcium.

The Effects of Dietary Excesses in Animal Protein and Sodium on the Composition and the Crystallization Kinetics of Calcium Oxalate Monohydrate in Urines of Healthy Men*

Dietary excesses in animal protein and/or salt have been implicated as risk factors in calcium oxalate urolithiasis. The underlying physicochemical mechanism is, however, not known. Eight healthy men were given four different diets varying in animal protein and in sodium content for 1 week each. On a high protein intake (2 g/kg.day) significant changes in urinary calcium, uric acid, and citrate excretion rates were found. Similar changes in calcium and citrate were induced by a high sodium intake (310 mmol/day). The changes were more pronounced when a high protein was combined with a high sodium diet. Urinary calcium increased from 3.79 +/- 0.31 to 6.42 +/- 0.61 mmol/24 h and urinary uric acid from 4.69 +/- 0.26 to 8.0 +/- 0.47, whereas urinary citrate decreased from 3.93 +/- 0.53 to 2.79 +/- 0.34 mmol/24 h. All three dietary regimens induced a significant decrease in the ability of urines to inhibit calcium oxalate monohydrate crystal agglomeration, which was most marked during the combined diet (from 345 +/- 39 to 205 +/- 28 min). The ability of urines to inhibit crystal agglomeration was related to their citrate content (r = 0.69, P less than 0.0001). These results show that high animal protein and/or sodium intake decrease the ability of urines to inhibit the agglomeration of calcium oxalate crystals and provide a possible physicochemical explanation for the adverse effects of dietary aberrations on renal stone formation.

Effects of Magnesium Salts in Preventing Experimental Oxalate Urolithiasis in Rats

Magnesium oxide, magnesium hydroxide, magnesium sulfate, magnesium trisilicate, and magnesium citrate were added to a calcium-oxalate lithogenic diet in order to determine their effects in preventing lithogenesis. Male Wistar-strain rats which had been fed the glycolic-acid diet developed marked urinary calculi within four weeks. Rats in the magnesium-hydroxide, magnesium-citrate, and magnesium-trisilicate groups, however, had almost no stones in the urinary system. Rats in the magnesium-oxide and magnesium-sulfate groups showed significantly less effect than those in the former three groups. During the experimental period, the 24-hour urinary oxalate excretion and concentration were higher in the glycolic-acid group than in the other groups. The urinary citrate excretion and concentration were the highest in the magnesium-hydroxide and magnesium-citrate groups and higher in the magnesium-trisilicate and magnesium-oxide groups than in the magnesium-sulfate and glycolic-acid groups. Similar trends were observed in the urinary magnesium excretion and in its concentration. The urinary calcium excretion and concentration were higher in the experimental groups than in the glycolic-acid group. The urinary calcium/magnesium ratio remained mostly unchanged. Therefore, it can be concluded that alkaline magnesium salts increase the urinary calcium and magnesium concentrations, without changing the calcium/magnesium ratio, and inhibit urinary calculi formation, most likely by increasing the urinary citrate concentration. (J. Urol, 144: 385-389, 1990)

尿路結石症における尿中イオン化カルシウム定量に関する研究とその臨床的意義

The concentration of urinary ionic calcium was estimated using an ion-selective electrode and ion analyzer for healthy controls and patients with calcium urolithiasis. The following results were obtained: 1) After calculating the ionic strength and calibrating the standard solutions of ionic calcium in each urine, the urinary ionic calcium was estimated using an ion-selective electrode and ion analyzer. The reproducibility and accuracy of the value of urinary ionic calcium were satisfactory. 2) There was a significant correlation between the concentration of urinary ionic calcium and the total calcium excretion. Although the percentage of ionic calcium did not show any correlations among the total calcium, oxalate and urinary pH, it had an inverse relation to urinary citrate and phosphate. 3) In calcium stone formers, the excretion of ionic calcium was higher than in healthy controls significantly. 4) In hypercalciuric calcium stone formers, the concentrations and excretions of total and ionic calcium were significantly higher than in normocalciuric calcium stone formers. However, the percentage of ionic calcium was not different. 5) When the patients were treated with citrate orally, the excretion of urinary citrate was increased, and the excretion of ionic calcium and the percentage for total calcium were decreased significantly. There were significant reductions of ionic calcium in the urine after oral administration of rice-bran. 6) The estimation of urinary ionic calcium might be important to evaluate the urinary risk in recurrent calcium stone, and to estimate the effects of the preventive treatments for its recurrence.

Crystal agglomeration is a major element in calcium oxalate urinary stone formation

The effects of urines from 36 healthy subjects and 86 calcium oxalate renal stone formers on calcium oxalate monohydrate crystallization kinetics were studied using a seeded crystal growth method in which the solubility, the growth and the agglomeration of the crystals are measured as three separate and system-independent parameters. The urines of healthy subjects were found to increase the solubility and to strongly inhibit the growth and the agglomeration of calcium oxalate monohydrate crystals. The urines of stone formers had a similar effect on the solubility, but a significantly lower ability to inhibit the crystal growth and the crystal agglomeration. Of these two kinetic processes the inhibition of crystal agglomeration was more clearly affected, with 55% of the stone formers having abnormally low values, while the changes in crystal growth inhibition occurred within the normal range. The defect in crystal agglomeration inhibition was related to stone frequency, and urines from patients with very high stone frequency rates had also the most severely impaired ability to inhibit the agglomeration of the calcium oxalate monohydrate crystals. The inhibitory effect of urines on crystal agglomeration was found to be related to its citrate content (r = 0.68, P less than 0.001). All patients with hypocitraturia, except two, had also abnormally low values for crystal agglomeration inhibition. In a group of 15 hypocitraturic stone formers, alkali treatment for a mean period of 18 months resulted in a parallel increase in urinary citrate excretion and in the ability of urines to inhibit crystal agglomeration (r = 0.77, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of allopurinol to modify urinary composition in enteric hyperoxaluria.

Conventional treatment of enteric hyperoxaluria (EHO) consists of dietary restriction of oxalate and fat and correction of its underlying cause whenever possible. Recent work suggests that allopurinol reduces the incidence of urolithiasis and the urinary excretion of both oxalate and uric acid in patients without intestinal disease. We have assessed the effect of allopurinol, 300 mg daily for 2 weeks, on urine biochemistry in patients with EHO due to small bowel Crohn's disease and/or resections. Compliance with treatment was confirmed by a fall in plasma uric acid in every patient. Allopurinol failed to alter 24 h urinary oxalate excretion or oxalate concentration. There were also no significant changes in the urinary excretion of glycollate (like oxalate, a breakdown product of glyoxylate), citrate, magnesium or calcium, each of which was at the lower end of the normal range before and during treatment with allopurinol. It appears unlikely that allopurinol will prove useful in the prevention of urolithiasis in patients with EHO.

Alterations in rat bone composition related to polyol supplementation of the diet

The effect of dietary supplements of xylitol, sorbitol and glucose on bone composition was studied in rats. The supplementation, expressed as a % of the dry diet, was gradually increased up to 20% over 3 weeks and continued for 5 weeks. The control group was fed a stock diet only. Each group consisted of nine rats aged 12 weeks at the beginning of the experiment. Ca, Mg, P, CO 3 and citrate were analysed from the femur and Ca and citrate also from the serum and urine. The results showed that xylitol supplementation significantly increased the concentrations of Ca and citrate in bone ( P < 0.001) and sorbitol that of Ca only, whereas glucose slightly reduced both CO 3 and citrate. The citrate concentration was found to correlate significantly with Ca and P ( P < 0.001), and also with Mg ( P < 0.002). Both xylitol and sorbitol increased serum Ca and the urinary excretion of Ca and citrate. In conclusion, high xylitol or sorbitol supplementation affects Ca and citrate metabolism. The results suggest a connection between citrate and Ca in bone.