In order to evaluate the decrease of uric acid excretion as the cause of diuretic-induced hyperuricemia in experimental animals, clearance studies were performed using rats treated with furosemide and trichlormethiazide. Acute administration of test diuretics at highly potent doses elevated the hematocrit, and decreased the inulin clearance, the urine-excreted amount of uric acid, the uric acid clearance and the fractional excretion of uric acid. The pyrazinoic acidsuppressible fractional excretion of uric acid was similar to those of both the control and diuretic-treated groups, which suggests accelerated uric acid reabsorption following diuretic administration. Consecutive administration of trichlormethiazide in rats fed a low-sodium diet resulted in marked diuresis, body weight loss, hemoconcentration and hypokalemia. In these volume-depleted rats, inulin clearance, the urine-excreted amount of uric acid, uric acid clearance and the fractional excretion of uric acid clearly decreased. This indicates the importance of fluid volume contraction on both the decrease in the filtration rate and the change in the transtubular uric acid transport. From the present findings, we concluded that the characteristics of the diuretics acting on uric acid retention could be understood in the experiments using rats.
Uric acid is present as monosodium urate (NaHU) for dissociation of about 99% in the blood and tissue fluid. NaHU being freely permeable through the capillary wall, the uric acid concentration is nearly equilibrated between blood and tissue fluid; consequently, to measure the serum uric acid level means indirect measurement of the uric acid concentration in the tissue fluid. Since pathogenecity of uric acid in the organism is manifested by precipitation of NaHU following its saturation in the tissue fluid, we consider that the solubility of NaHU in the tissue fluid is an indispensable factor in determining the normal range of the serum uric acid level. However, the composition of tissue fluid is somewhat varied in the sites of body, and it is also difficult practically to collect tissue fluid for determination of the solubility of NaHU. In an attempt to solve this problem, we prepared an experimental solution consisting of composition similar to the tissue fluid and determined the solubility of NaHU in the solution to obtain an approximate value of the solubility of NaHU in the authentic tissue fluid. And the following results were obtained: 1) The saturated concentration of NaHU in the experimental tissue fluid of which protein level is 0 was 6.8 mg/dl at 37°C. 2) The saturated concentration of NaHU in the experimental tissue fluid of which protein level is 7.46 g/dl (same as serum) was 12.5 mg/dl at 37°C.
A 48, XXYY syndrome, a rare variant of Klinefelter's syndrome, was recognized through chromosome analysis in a 34-year-old Japanese male with hypogonadism. On routine laboratory examinations, he also had hypouricemia (1.7-2.6 mg/dl). Oral administration of inosine resulted in increases in serum and urinary urate concentrations, suggesting that endogenous urate synthesis from inosine was not disturbed. Renal clearance ratio of urate to creatinine (CUA/Ccr) increased markedly after an oral administration of probenecid. The decrease in CUA/Ccr after pyrazinamide administration seemed almost normal. The above data show that the hypouricemia in the patient is due to the isolated renal tubular abnormality. Several mechanisms for renal hypouricemia have been proposed which include three types of reabsorption defect and an abnormality with increased urate secretion. The present patient would be considered to be a case of incresed renal tubular urate secretion. The family study has suggested that the renal hypouricemia in this patient is of hereditary nature. Further investigations are needed to elucidate whether any etiological relationship exists betweeen renal hypouricemia and XXYY syndrome.
The renal clearance studies and pyrazinamide (PZA) suppression tests were performed in uncomplicated diabetics.1) The uric acid clearance (Cua) in diabetics was higher than that in normal subjects. The higher blood glucose was, the higher Cua was trend to be. Significant positive correlations between FBS and Cua or Cua/Ccr ratio were found. The Cua decreased as blood sugar reduced to normal range by treatment. Urinary uric acid (Uua) excretion increased when urine sugar increased in volume. 2) A significant negative correlation between Cua and SUA, and significant positive correlation between Cua and Uua were found. 3) After PZA administration, SUA was unchanged, but Cua, Cua/Ccr ratio were markedly reduced. Reabsorption rate of urate in the tubule and secretion rate were higher and lower in diabetics than in normals respectively. The above results indicated the possibility of the inhibition of postsecretory reabsorption of urate in the distal tubule.
Uric acid is the end product of purine metabolism, and hypoxanthine is the precursor of uric acid in human. Some studies on cerebrospinal fluid (CSF) uric acid and hypoxanthine in patients with various neurological diseases were reported in the literature. In this study we discussed the clinical value of the measurement of CSF uric acid and hypoxanthine levels in patients with brain tumor. CSF was investigated for uric acid and hypoxanthine in 23 normal controls and 30 cases with brain tumor. The results as follows; 1) The mean values and standard deviations of uric acid and hypoxanthine level in normal controls were 0.23±0.13 mg/dl,0.07± 0.03 mg/dlrespectively. 2) The CSF uric acid levels increased in patients with malignant brain tumor, but were normal range in patients with benign tumor. 3) The CSF hypoxanthine levels were normal range in patients with benign or malignant brain tumor. 4) Uric acid in lumbar CSF were approximately 4 times higher than that in ventricular CSF in patients with brain tumor. On the contrary, hypoxanthine levels were not different in both CSF. 5) The CSF uric acid and hypoxanthine levels had increased progressively in spite of decreasing in tumor size while the irradiation was performed to the whole brain. 6) It was suggested that the measurement of CSF uric acid and hypoxanthine levels were useful to find the subclinical condition of the patients with cerebral diseases, however the dynamic conditions in a multi-components system like this were extremely complicated.
There has been no indices to decide a suitable prophylaxic management for error of urate metabolism. It is not possible under present conditions to establish the precise definition even using serum and urinary uric acid level. Therefore, we have aimed in the present studies to elucidate an index to take measures for prophylaxis in metabolic error. The cocentration of serum uric acid and the excretion of urine uric acid were determined in 161 cases of normal human. Urine uric acid level was 660.7±169.8 mg/24 hrs (M±S.D.) in 120 normal males and 593.6±147.9 mg/24 hrs (M±S.D.) in 41normal females. Furthermore, it was concluded that there was significant correlation between urine uric acid level and creatinine clearance rate. The ratio of urine uric acid per creatinine clearance rate (Uur/Ccrea) was 8.6±1.8 (M±S.D.) in l20normal males and 7.5±1.6 (M±S.D.) in 41 normal females. The standard deviation in Uur/Crea showed markedly lesser value than that in urine uric acid level. It is strongly suggested that Uur/Crea may become an useful index for prophylaxic management in patients with the metabolic error. Based on this, Uur/Ccrea in 363 patients with urolithiasis were determined. Furthermore,78 cases with the metabolic error were treated with allopurinol in part probenecid for one to 14 years. Getting together, the results were summarized as follows. 1) In generally, the treatment with allopurinol revealed a tendency to decrease in formation of stone. Especially, in patients with pure uric acid urolithiasis and other stones with gouty attack, the treatment could completely prevent for recurrent stone. 2) Recurrent formation of stone as recognized in 11 cases during the treatment, Uur/Ccrea in 8 patients out of cases, who were made diagnosis of hyperuricosuria, remained within normal range.3 out of the cases had chronic urinary infection. It is resulted in the present studies that Uur/Ccrea may be an effective marker to detect the patient who should be appropriated the long term treatment for error of urate metabolism.
We studied serum uric acid levels in association with the clinical complications in human dock examinees which consist of 3056 public school teachers (2020 males and 1036 females). The following results were obtained. 1. Mean±SD in serum uric acid concentration were 5.54±1.25mg/dl for males and 4.38±0.97 mg/dl for females. It was regular distribution in females, but there was tendency to deviate toward higher levels in males. 2. There were no significant differences in serum uric acid levels from age 30 to 69 in both sexes. But, serum uric acid levels in females increased after menopause. 3. Serum uric acid value increased in proportion to the degree in their body weight. 4. The frequency of gouty attack in the past history was 2.1%(43/2020) for males and 0.5% (5/1036) for females. 5. The frequency of hyperuricemia was 5.8% (60/1036) for females (serum uric acid value>6 mg/dl) and 12.7% (257/2020)(U. A.>7 mg/dl) or 4.0% (81/2020) for males (U. A.>8 mg/dl). 6. There were no significant differences in dose of drinking alcohol between normal group and hyperuricemia group. 7. The proportion of obesity in hyperuricemia group was more than that in normal group. 8. Hyperuricemia group showed much higher frequency of having associated complications such as hyperlipidemia, hypertension and renal dysfunction (serum creatinine>1.2 mg/dl)than normal group.
To clarify the relationship between acidity of urine and uric acid metabolism, especially under excretion of urate, urine pH was determined before each meal in 139 gouty patients for 2-4weeks. Urine pH was correlated with urate metabolism coefficients such as serum urate level (Sua), urinary excretion (Uua), urate clearance (Cua), creatinine clearance (Ccr) and clearance ratio (R) as determined by the urate clearance test previously reported. The ratio of patients with acidic urine w as higher in the group with severe under excretion than in that with overproduction, but no significant correlation was observed between the urate metabolism coefficients and urine pH in these patients(X25.2<X20.05=15.5). Administration of 3.0 gr of Uralyt U daily caused a significant increase in urine pH (P<0.01) which was of a lesser grade in the morning urine, but no evidence of increasing urate excretion was found. In daily profile of urine pH in a normal subject, urine pH was low before meals especially before breakfast but a transient increase was seen 2-3 hours after meals, probably due to the acid-base balance of the administered diet.
This study was performed to examine whether exerciseinduced hyperurico-phenomenon depended on increased production of uric acid or decreased renal excretion of uric acid. Exhaustive exercise on treadmill was performed i n 5 healthy subjects, mean age 22 years (20-24). In allopurinol exper iment, the subjects were administered 200 mg of allopurinol after breakfast 2 hours prior to exercise. In benecid experiment,1000 mg of benecid was administered. No drug was administered in control experiment. In three experiments, we had no differencein VO2max, HRmax, running time, blood lactate and serum CPK. There was no significant difference in urinary excretion of 3-methylhistidine. The elevation of serum uric acid was the highest in control experiment (+1.56 mg/dl at 1 hour after exercise), which did not return to the initial level even 7 hours after exercise. The serum uric acid concentration of benecid experiment increased as much as control experiment 1 hour after exercise (+1.23 mg/d1), decreased after that and remained below the initial level since 3 hours after exercise. However, no increase of serum uric acid was observed in allopurinol experiment, which remained till 7 hours after exercise. On the other hand, urinary excretion of uric acid, uric acid clearance, creatinine clearance and clearance ratio were maintained higher level in benecid experiment than in other experiments. These observations suggest that increased production of uric acid had more influence on the appearance of exerciseinduced hyperurico-phenomenon than decreased renal excretion of uric acid.
The author investigated the various factors affecting serum uric acid (SUA) level in patients with diabetes mellitus and the following results were obtained. 1) The levels of SUA in male patients were higher than that in female ones and were trend to increase among young groups. 2) The levels of SUA in diabetics With both obesity and hypertriglyceridemia significantly increased. However, a single factor such as obesity, hypertension, hypercholesterilemia and hypertriglyceridemia did not increase the SUA levels. 3) Fasting blood glucose (FBG) was negatively correlated to the SUA level. The SUA level increased as FBG lowered and urine sugar decreased.
To investigate the uric acid production in patients with diabetes mellitus, serum adenosine deaminase (ADA) activity was determined and the following results were obtained. 1) The ADA levels in diabetics were not different compared with those in normals. The ADA levels in the group with fasting blood sugar (FBS) over 150 mg/dl were significantly higher than those with FBS below 130 mg/dl. 2) There were no significant correlations between the ADA levels and the serum uric acid levels and the urinary uric acid. The above results indicated the possibility of inc r e ase in uric acid production in diabetics.
In patients with a congenital adenine phosphoribosyltransferase (A-PRTase) deficiency, urolithiasis caused by the formation of 2,8-dihydroxyadenine is observed from infancy. Since 2,8-dihydroxyadenine is very insoluble in water, it is a nephrotoxic, and is now known to cause serious renal insufficiency. Authors treated a girl with this disease by oral administration of Alositol (from Tanabe Seiyaku Co., Ltd. ), which is an allopurinol preparation. Authors made use of our finding that 2,8-dihydroxyadenine crystals was always excreted in her urine so that the drug's inhibitory effect on the excretion of these crystals could be recognized. As a result, authors found that a single administration of 2.0 mg/kg allopurinol was insufficient, but that 3.3 to 4.5mg/kg/day would inhibit the excretion of crystals. It was conculuded therefore that in con g enital A-PRTase deficiency, when 2,8-dihydroxyadenine crystalluria is noted, the necessary dose of allopurinol preparation for the prevention of urolithiasis and renal insufficiency, may constitute a criterion for the effective dose to inhibit the excretion of crystals.