Effect of Frusemide,Lactose, and Urea on Urinary Cell Loss

With the use of a staining method by which cells in the urine can be differentiated, the effect of oral frusemide, lactose, and urea on the rate of excretion of these cells was investigated in five healthy persons.It is shown that frusemide greatly increases the urinary excretion of red cells, white cells, and renal tubular cells. Similar though not so marked changes were produced by both lactose and urea. Possible reasons for the increased excretion of cells are discussed. One is that it may be the result of an increase in the rate of urinary flow.     

Reduction of the effects of diuretics or sodium chloride loading in the conscious rat by inhibitors of prostaglandin synthesis

In conscious rats pretreatment with indomethacin or flurbiprofen, two chemically unrelated inhibitors of prostaglandin synthesis, reduced urine volume and sodium excretion induced by four diuretics, acetazolamide, amiloride, bendrofluazide and frusemide, or oral sodium chloride loads. The maximum reduction in sodium excretion was limited to approximately 2 mmol/kg Na⁺ even when sodium excretion was greatly increased. In contrast these inhibitors did not appreciably affect potassium excretion. These results indicate that part of the natriuretic response in the rat to highly and moderately efficacious diuretics and to sodium chloride loading is modified by prostaglandins. We suggest that the lack of effects on potassium excretion indicate that the collecting tubule is the probable site of action.     

Influence of a high protein diet on the urinary and fecal excretion of calcium in albino rats

Albino rats (Sprague-Dawley) of mean weight 100 g were divided into four groups and given for 7 days a balanced diet. They were then placed in metabolic cages for fifteen days and fed diets containing different quantities of casein: 18% (D18), 36% (D36), 50% (D50) and 72% (D72). The levels of total calcium, inorganic phosphorus, alkaline phosphatase activity, total proteins and urea were determined. The urinary and fecal excretion of calcium were determined on specimens of urine and stool collected every two days. The metabolic balance of nitrogen was also estimated. The results show there is not a linear relationship between a high protein diet and plasma protein levels, but a progressive body calcium loss was observed with the increase of casein in the diet, which confirms what other workers have already suggested.     

Urinary excretion of electrolytes during prolonged physical activity in normal man

Nine normal young male students were studied during 2 days of relative rest, during 2 days of physical training and again during the succeeding 2 days of relative rest. Twenty-four hour urine collections showed that sodium and potassium excretion were lower during the exercise days, while urinary aldosterone excretion was increased. No differences in the 24-h urinary excretion of creatinine, calcium, and magnesium were found between the resting and exercise days. Hemoglobin concentration, hematocrit and red cell counts were decreased at 14 h and 42 h after exercise; these findings together with the increased serum bilirubin concentration could result from hemolysis. Plasma renin activity, angiotensin II and aldosterone concentration were increased 14 h after exercise but returned to baseline 42 h after exercise. Our data shows that one should take into account previous exercise when interpreting results of certain of these tests.     

Biochemical variables in plasma and urine before and after prolonged physical exercise

Nine normal young male students were studied during 2 days of relative rest, during 2 days of physical training and again during the succeeding 2 days of relative rest. 24-hour urine collections showed that the creatinine, creatine, uric acid, urea, calcium and magnesium excretion were similar during the resting and exercise days. The 24-hour urinary excretion of sodium and potassium was decreased during the exercise days, while the aldosterone excretion was increased. The hemoglobin concentration, hematocrit and red cell counts were decreased 14, as well as 42 h after exercise. The serum uric acid, creatine phosphokinase-MM (skeletal muscles) subfraction, glutamic oxalacetic transaminase and myoglobin levels were increased 14 h after exercise, but returned to baseline 42 h after this type of exercise. The mechanisms of these alterations were discussed and the data show that one should take into account previous exercise when interpreting the results of certain of these tests.     

A Pilot Study of the Effect of Sodium Thiosulfate on Urinary Lithogenicity and Associated Metabolic Acid Load in Non-Stone Formers and Stone Formers with Hypercalciuria

Background and Objectives

Sodium thiosulfate (STS) reduced calcium stone formation in both humans and genetic hypercalciuric stone forming (GHS) rats. We sought to measure urine chemistry changes resulting from STS administration in people.

Design, Setting, Participants & Measurements

STS was given to healthy and hypercalciuric stone forming adults. Five normal non-stone forming adults (mean age 33 years), and 5 people with idiopathic hypercalciuria and calcium kidney stones (mean age 66 years) participated. Two baseline 24-hour urine collections were performed on days 2 and 3 of 3 days of self-selected diets. Subjects then drank STS 10 mmol twice a day for 7 days and did urine collections while repeating the self-selected diet. Results were compared by non-parametric Wilcoxon signed rank test. The primary outcome was the resulting change in urine chemistry.

Results

STS administration did not cause a significant change in urinary calcium excretion in either group. In both groups, 24 hour urinary ammonium (P = 0.005) and sulfate excretion (P = 0.007) increased, and urinary pH fell (P = 0.005); citrate excretion fell (P<0.05) in hypercalciuric participants but not in non-stone formers. Among stone formers with hypercalciuria, 3 of 5 patients had measurement of serum HCO₃ concentration after the STS period: it did not change. The net effect was an increase in supersaturation of uric acid, and no change in supersaturation of calcium oxalate or calcium phosphate.

Conclusions

The basis for studies demonstrating that STS prevented stones in rats and people was not reflected by the changes in urine chemistry reported here. Although serum HCO₃ did not change, urine tests suggested an acid load in both non-stone forming and hypercalciuric stone-forming participants. The long term safety of STS needs to be determined before the drug can be tested in humans for long-term prevention of stone recurrence.     

Idiopathic calcium nephrolithiasis. 2. Differences between hypercalciuric and normocalciuric persons with recurrent kidney stone formation and persons without such a history.

Normocalciuric and hypercalciuric patients with idiopathic recurrent calcium nephrolithiasis were compared with healthy individuals without such a history to examine the factors that predispose normocalciuric patients to stone formation. The urine calcium excretion rate was higher in the normocalciuric patients than in the control subjects (227 v. 183 mg/24 h; P less than 0.01), but the urine calcium concentration was not significantly different. The urine magnesium and citrate excretion rates and concentrations were lower in the normocalciuric patients than in the control subjects (P less than 0.001), while the urine uric acid and oxalate excretion rates and concentrations and the urine saturation with brushite (CaHPO4-2H2O) were not significantly different. These results suggest the importance of slight increases in the urine calcium excretion rate together with decreased urine magnesium and citrate excretion rates in normocalciuric persons with recurrent calcium stone formation. The urine of the hypercalciuric patients was more highly saturated with brushite than the urine of the normocalciuric patients and the control subjects, and the excretion rates of uric acid and oxalate were increased in the hypercalciuric patients. The hypercalciuric patients had a higher urine creatinine excretion rate than the normocalciuric patients and a higher daily urine volume than the control subjects, which suggests that differences in lean body mass or fluid and food intake, or both, may be important determinants of these differences in crystalloid excretion. As in the normocalciuric patients, the urine citrate excretion rate and concentration were decreased in the hypercalciuric patients compared with the control subjects.     

Biological effects of the enhanced excretion of zinc after calcium diethylenetriaminepentaacetate chelation therapy.

An enhanced, uncompensated excretion of zinc may be responsible for unwanted side-effects that could develop after prolonged chelation therapy with calcium diethylenetriaminepentaacetate (Ca-DTPA). As a preliminary means of defining "potential toxicity" within this hypothesis, the "normal" concentration range of Zn++ excreted in the urine of three adult female baboons was measured on a daily basis; changes in urinary Zn++ excretion were then quantitated as a function of the injection time and dose of the chelating agent Na3(Ca-DTPA) originally administered to enhance the excretion of 241Am from the body. In addition, the inhibitory action of the chelator compound on the activity of a specific metalloenzyme system, erythrocytic aminolevulinic acid dehydratase (ALAD), which requires Zn++ as a co-factor, has been determined as a measure of a specific biological effect. It was found that whenever the concentration of Zn++ in urine was above 2 mug/ml (or greater than approximately four times the "normal" urinary excretion level), the activity of ALAD dropped below 250 nmol PBG/ml RBC/hr or approximately one-half the mean "normal" activity value for this primate species.     

Idiopathic calcium nephrolithiasis. 1. Differences in urine crystalloids,urine saturation with brushite and urine inhibitors of calcification between persons with and persons without recurrent kidney stone formation.

The propensity of urine to promote calcium stone formation was compared in 64 patients with recurrent idiopathic calcium nephrolithiasis and 30 healthy individuals without such a history. The rates of excretion of urine crystalloids, the urine saturation with brushite (CaHPO4-2H2O), the ability of the urine to calcify collagen in vitro, and the concentration of urine inhibitors of collagen calcification were measured. The patients had a reduced urine citrate excretion rate in addition to an increased urine calcium excretion rate, while the rates for urine magnesium, phosphate, uric acid and oxalate were not significantly different in the two groups of subjects. The urine concentration of magnesium, phosphate and uric acid was decreased in the patients because of the higher urine volume. The urine creatinine excretion rate correlated with the rates of excretion of urine calcium, magnesium, phosphate, uric acid and oxalate in both groups, which suggested that increased lean body mass, possibly associated with greater food intake, may be an important determinant of crystalloid excretion. The urine of the patients was significantly more saturated with brushite than the urine of the control subjects and resulted in greater collagen calcification when incubated in vitro. The urine concentration of inhibitors of collagen calcification, however, was not significantly different in the two groups. Thus, the urine of patients with recurrent idiopathic calcium nephrolithiasis is more highly saturated with brushite, largely as a result of an increased urine calcium excretion rate, and contains a lower concentration of magnesium and citrate, substances that tend to prevent the precipitation and growth of crystals in urine.     

Excretion of Urinary Casts after the Administration of Diuretics

The administration of ethacrynic acid and frusemide to healthy volunteers was regularly followed by the excretion of hyaline casts, without any concomitant proteinuria. Hydrochlorothiazide and chlorthalidone did not themselves induce cylindruria but augmented that provoked by acidifying agents. It was shown by the indirect immunofluorescence method that the casts were composed of uromucoid (Tamm-Horsfall mucoprotein), which is always present in the urine, usually in solution, and originates predominantly from the tubule cells of the ascending limb of Henle''s loop. The urinary excretion of Tamm-Horsfall mucoprotein was not increased after the administration of ethacrynic acid. This mucoprotein is precipitated and forms aggregates when the concentration of electrolytes increases and when the pH of the urine declines. The casts that appear in the urine after strenuous physical exertion are of essentially the same composition. Casts produced by patients with kidney diseases, on the other hand, contain various protein fractions derived from the blood as well as mucoprotein. Cylindruria occurring during diuretic therapy and physical exertion is of no pathological significance, and the diagnostic value of byaline casts is very much limited if their exact composition cannot be determined.     

Comparison of calcium oxalate values as indicators of risk for calcium oxalate calcinosis and the degree of urine saturation in patients with calcium urolithiasis and in healthy patients

Daily excretion of calcium, magnesium, oxalates, and citrates together with daily urine output were determined in 37 patients with calcium urolithiasis and in 25 healthy individuals. Basing on the obtained values, a degree of urine saturation with calcium oxalate with Marshall and Robertson technique and a value of risk factor with Tiselius technique were calculated. It was found that daily diuresis and excretion of calcium with the urine are significantly higher in patients with urolithiasis where as daily excretion of citrates with the urine is significantly lower than in healthy individuals. Risk index proved two-fold higher in the examined patients than in the healthy individuals (p greater than 0.001) while the degree of urine saturation with calcium oxalate did not differ significantly in both groups. The authors, discussing causes of seemingly different changes in both tested parameters, stressed diagnostic value of risk index which includes excretion of crystallization inhibitors (magnesium, citrates) and contrary to the degree of urine saturation is independent of daily urine output.     

Seasonal Variation in Urinary Excretion of Calcium, Magnesium and Phosphate in Manic-Melancholic Patients

The 24-hr urinary excretion of calcium, magnesium and phosphate was measured in 76 normal control persons, 95 manic-melancholic patients not on lithium treatment and 74 lithium-treated manic-melancholic patients. The mean value of the urinary excretion for each of the four seasons during a 5-year period was calculated. The normal control persons had a higher excretion of calcium during the summer months than during the rest of the year; this seasonal variation was not present in the two groups of manic-melancholic patients.

Previously reported changes in electrolyte metabolism during lithium treatment were confirmed, but some of the results varied with the season.     

Abnormal calcium metabolism in normocalcaemic sarcoidosis.

In studies of calcium metabolism in 13 unselected patients with untreated sarcoidosis all were normocalcaemic but five had hypercalcuria. All had normal renal function. Calcium absorption was indexed by a double isotope test. 45Ca hyperabsorption occurred in six patients. Ten kinetic studies were carried out with 47Ca and in six bone turnover was increased. 45Ca absorption correlated well with the calculated bone uptake rate of calcium, and with urine calcium excretion. These results suggest that in sarcoidosis abnormalities in calcium metabolism are fairly common although they rarely result in sustained hypercalcaemia.     

Total Body Potassium in Long-Term Frusemide Therapy: Is Potassium Supplementation Necessary?

Measurements of total body potassium (T.B.K.) were made by whole-body counting in four groups of patients receiving oral frusemide for one year. Patients in group 1 had essential hypertension and normal renal function and received 40 mg frusemide daily without potassium supplements. Patients in group 2 were similar but received oral potassium supplements for the first four months of treatment. Patients in group 3 had hypertension associated with renal disease and received 120 mg frusemide daily without potassium supplements. Patients in group 4 also had hypertension and renal impairment and in addition to 120 mg frusemide daily they received oral potassium supplements for four months. No evidence of depletion of T.B.K. was found in any of the groups after continuous treatment with frusemide for one year. It is questioned whether potassium supplementation in long term diuretic therapy with frusemide is necessary unless there is evidence of pre-existing potassium depletion or of some other factor such as cardiac failure, cirrhosis of the liver, or the nephrotic syndrome.     

Effect of prostaglandin inhibition on caffeine-induced hypercalciuria in healthy women

Caffeine ingestion increases urinary calcium excretion. The mechanism is not known, but prostaglandin synthesis has been implicated. We hypothesized that administration of a prostaglandin inhibitor such as acetylsalicylic acid (aspirin) along with caffeine would prevent caffeine-induced hypercalciuria. We measured 3-hour excretion in fasting subjects who each randomly ingested four treatments on nonconcurrent mornings: no drug, caffeine (5 mg/kg body weight), acetylsalicylic acid (650 mg), or caffeine plus acetylsalicylic acid. In experiment 1, nine healthy premenopausal female subjects were studied; each treatment was taken with 200 ml of orange juice. Water was provided hourly to encourage urine flow. Urinary calcium excretion rose with caffeine treatment; mean 3-hour calcium (mmol/mmol creatinine) was 0.49 +/- 0.07 compared with 0.23 +/- 0.04 during the no-drug treatment. Acetylsalicylic acid caused a significant reduction in urinary calcium to 0.13 +/- 0.08; when it was combined with caffeine, caffeine-induced calcium excretion fell significantly to 0.35 +/- 0.08. Sodium excretion tended to reflect calcium excretion. Urinary prostaglandin E(2) fell significantly with acetylsalicylic acid, with and without caffeine. There were no significant changes in creatinine, water, or potassium excretion. Experiment 2 was similar, except that water was substituted for orange juice to test the possibility that acetylsalicylic acid affected elevated but not basal calcium excretion. Similar and even more pronounced results were obtained, with caffeine causing a threefold increase in urinary calcium, acetylsalicylic acid causing a decrease by half, and the combined drug treatment being greater than no drug but less than caffeine alone. Urinary phosphorus rose significantly with caffeine alone. Prostaglandin synthesis may not be directly involved in caffeine-induced hypercalciuria, as the magnitude of the caffeine-induced increase was similar when treatments given the acetylsalicylic acid were compared with those without a prostaglandin synthesis inhibitor.     

Bumetanide: Potent New “Loop” Diuretic

Bumetanide, a pharmacologically new diuretic, was evaluated in 27 subjects. Its onset of action was within 30 minutes with a peak at 90 minutes and a total duration of action of about 270 minutes. In a controlled study in oedematous patients it was equipotent with frusemide at one-fortieth the molar dosage and did not differ from frusemide with regard to its pattern of electrolyte excretion. On continuous oral administration for eight days it produced effective diuresis with minimal alteration in biochemical and haematological status. The only adverse effect was gastric discomfort in one patient.     

Effect of hydrochlorothiazide on urine saturation with brushite,in vitro collagen calcification by urine,and urinary inhibitors of collagen calcification

To clarify further the beneficial effect of thiazide diuretics on recurrent calcium nephrolithiasis, the effect of short-term hydrochlorothiazide therapy on urine saturation with brushite (CaHPO₄·2H₂O), in vitro collagen calcification by urine, and urinary inhibitors of calcification was studied.In 22 patients with idiopathic calcium oxalate/phosphate stones the urine calcium excretion decreased, the urine magnesium excretion increased and the urine magnesium/calcium ratio increased significantly (P < 0.001) during hydrochlorothiazide therapy. Supersaturation of the urine with brushite, which was present in 19 of the 22 patients, was reduced significantly (P < 0.001) in all during thiazide therapy, and to the undersaturated range in 16. The ability of urine to calcify collagen in vitro also decreased significantly (P < 0.001) during thiazide therapy, a change that correlated significantly (r = 0.4513, P < 0.05) with the decrease in brushite saturation. The concentration of urinary inhibitors of calcification, as determined with an in vitro collagen calcification system, was decreased significantly (P < 0.01) by thiazide therapy.It was concluded that, in addition to decreasing urine calcium excretion and increasing urine magnesium excretion, thiazide diuretics decrease the urinary brushite saturation and thus may prevent spontaneous nucleation or crystal growth, or both, of calcium phosphate. The ability of thiazides to decrease collagen calcification in vitro suggests that they may also prevent crystal growth on a nidus of organic matrix. Thiazides do not appear to act by increasing the excretion of urinary inhibitors of calcification.     

The effects of hypophysectomy, prolactin therapy and environmental calcium on electrolyte balance of the brown trout Salmo trutta, L.

Adaptation of the brown trout to fresh water containing increasing concentrations of calcium resulted in a decrease in plasma electrolyte level and total electrolyte excretion. The electrolyte excretion rate was higher at the beginning than at the end of the urine collection periods. Hypophysectomized fish had a lower plasma electrolyte concentration than the controls. This deficiency was partially corrected by polactin therapy. High environmental calcium was only effective to a limited extent. There was no difference in the normal renal sodium output between hypophysectomized and intact fish in fresh water. Environmental calcium did not have any significant effect on renal electrolyte output of hypophysectomized fish.     

Effect of difructose anhydride III on calcium absorption in humans

The effects of difructose anhydride III (DFAIII) on stimulating calcium absorption was investigated in humans. We studied changes in the time-course of characteristics urinary calcium excretion in 12 healthy men given 0.3, 1.0 or 3.0 g of DFAIII and 300 mg of calcium as calcium carbonate. In addition, urinary excretion and urine concentrations of creatinine and deoxypyridinoline were determined. Urine calcium excretion every 2 hours after the intake were higher over than that of the control subjects. The total amount of urinary calcium excretion for 10 hours was significantly greates in the subjects given 1.0 g or 3.0 g of DFAIII than that of the control subjects. However, there were no differences in the urine concentrations of creatinine and deoxypyridinoline between the subjects given DFAIII and the control subjects. These findings suggests that low dose of DFAIII had a stimulating effect on calcium absorption in humans.     

Utilization of 15N-urea administered into the sheep small intestine.

The retention and excretion of intrajejunally administered 15N-urea was studied in four experiments on two sheep with a permanently fistulated small intestine. In the first 7 days after the administration of 2 g 15N-urea, 18.26% was excreted in the faeces and 19% in the urine; 62.74% was retained in the organism. Urinary excretion took place mainly on the first day and from the 3rd to the 7th day no 15N was present in the urine. The rate of 15N excretion in the faeces was roughly the same for the first 4 days and then fell; on the 7th day there was no 15N in the faeces. The proportion of 15N-urea retained in the organism and excreted in the urine was 81% showing that urea in the ruminant gastrointestinal tract is largely linked up into metabolic circulation as part of the general exchange of nitrogenous compounds.