The natural history of urate overproduction in sickle cell anemia.

Serum uric acid and uric acid excretion were studied in 95 patients with sickle cell anemia ranging in age from 17 months to 45 years to ascertain the natural history of urate overproduction. Hyperuricemia was infrequent in children with sickle cell anemia, but was found in 26 of 67 adults (39%). Thirty-six patients studied in a clinical research center had a mean urate clearance of 9.1 +/- 0.8 mL/min. Patients with sickle cell anemia were often normouricemic despite urate overproduction. Normouricemia was maintained by increased urate clearance, which was attributed to increased urate secretion. The hyperuricemic patients had decreased urate clearance with decreased pyrazinamide-suppressible urate clearance. Para-aminohippurate clearance was decreased to 634 mL/min in the hyperuricemic patients with sickle cell anemia compared with 853 mL/min in normouricemic hyperuricosuric subjects with sickle cell anemia. Hyperuricemia occurs only in patients who develop altered renal tubular function with diminished urate clearance secondary to diminished urate secretion.     

Diabetic renal hypouricemia

In diabetes, the serum uric acid level is low due to increased urate clearance; however, its mechanism remains unknown. We examined seven maturity-onset diabetic patients with rarely reported hypouricemia due to renal tubular abnormality to better understand the renal handling of urate by the diabetic kidney. The results of studies indicate that the increase in urate clearance was entirely accounted for by increased pyrazinamide-suppressible urate clearance. The maximal uricosuric response to probenecid administration was exaggerated. The effects of drugs on urate clearance were similar to those we have previously reported in the syndrome of inappropriate secretion of antidiuretic hormone. In four patients, the family survey did not reveal anyone with hypouricemia. These observations suggest that hypouricemia due to hyperuricosuria, which responds markedly to pyrazinamide and probenecid, is actually an indicator of renal tubular abnormality in diabetics.     

Uricosuric effect of irtemazole in hyperuricemic patients without and with renal insufficiency

A single oral dose of 50 mg irtemazole exhibited a clear cut uricosuric effect in five patients with hyperuricemia and normal renal function. The average maximal decrease of plasma uric acid was 46.1% compared to the initial value; it was reached between 6 h and 12 h after drug administration. Extent and course of plasma uric acid showed no differences between normouricemic (5) and hyperuricemic subjects. In four patients suffering from hyperuricemia and renal insufficiency only a minor effect of irtemazole was seen. The average maximal decrease of plasma uric acid reached 12.8% compared to the initial value. It occurred between 8 h and 12 h after drug ingestion. In both normouricemic and hyperuricemic subjects irtemazole acts more quickly than benzbromarone and probenecid. The duration of its uricosuric effect is shorter. Like benzbromarone, irtemazole exhibits only a minor effect in patients with reduced creatinine clearance.     

Renal handling of uric acid in gout: Impaired tubular transport of urate not dependent on serum urate levels

Metabolic studies were conducted in 56 patients with primary gout and in ten normal subjects to assess differences in the tubular transport mechanisms of urate. Renal handling of uric acid was examined by means of pyrazinamide and probenecid tests at increased and pharmacologically reduced serum urate concentrations in both groups. Patients with gout showed similar serum urate levels and glomerular filtration rates than controls at both serum urate levels. Pyrazinamide decreased urinary uric acid excretion to less than 1.0% of the urate filtered load in both groups at increased and diminished serum urate concentrations. The maximum uricosuric response promoted by probenecid at high serum urate levels was (mean +/- SD) 3,707 +/- 443 micrograms/min/1.73 m2 in controls and 2,215 +/- 738 micrograms/min/1.73 m2 in patients with gout (P less than 0.01). Forty-four patients had a daily uric acid excretion rate below 700 mg/1.73 m2, and all of them showed a diminished uricosuric response to probenecid. When serum urate was reduced in normal subjects and 30 patients to a mean of 2.1 and 2.3 mg/dL, respectively, probenecid elicited a significantly lower urate excretion rate in gout (532 +/- 202 micrograms/min/1.73 m2) than in controls (922 +/- 136 micrograms/min/1.73 m2; P less than 0.01). Among these 30 patients examined in their basal state and at decreased serum urate levels, uric acid excretion following probenecid was normal in six and diminished in 24 in both situations. The difference between maximum uricosuria and basal urate excretion was not increased in gouty patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

A SHORT TRIAL ASSESSMENT OF URICOSURIC THERAPY IN GOUT

A study has been made of the short-term effects of two uricosuric drugs (sulphinpyrazone and probenecid) in 12 gouty patients. The changes induced by these drugs on serum uric acid levels, 24-hour urate excretion rates and urate clearance values have been related to glomerular function. Since allopurinol is now available for the therapy of gout, and as uricosuric agents may fail to resolve tophaceous deposits, it is held that long-term uricosuric therapy should not be undertaken unless the efficacy of the chosen drug has been established. Therapeutic criteria have been proposed as a result of this trial. The magnitude of the urate diuresis induced by these drugs was found in general to be dependent on glomerular function; but even in the presence of a normal glomerular filtration rate a particular uricosuric drug could be ineffective. A glomerular filtration rate of less than 80 ml. per minute was associated with a relative failure of the drugs under trial, and it is considered that this level of renal impairment is an indication for the use of allopurinol. In the type of assessment described it is important that both the fall in the serum uric acid level and the rise in urate excretion should be estimated, for these changes do not under all circumstances bear a constant inverse relationship to one another.     

Renal transport of urate during diuretic-induced hypouricemia

The effect of two weeks administration of a uricosuric diuretic (SKF-62698) on renal urate handling has been examined in 11 normal men. Plasma urate concentrations had declined by more than 60 per cent after two weeks. Urate excretion per unit of glomerular filtration rate and urate clearance (C_urate) per unit of glomerular filtration rate were increased after the administration of SKF-62698. The importance of intact tubular secretion of urate in producing these changes was assessed by administering pyrazinamide, an agent that curtails urate secretion, to each participant. The decrements in urate excretion and clearance produced by pyrazinamide both increased significantly, whereas the residual urate excretion rates and clearances not suppressible by pyrazinamide were only minimally altered by SKF-62698 treatment. These results suggest that the excretion of secreted urate was enhanced by prolonged administration of SKF-62698, probably secondary to the inhibition of postsecretory urate reabsorption. In addition, because the nonsuppressible urate excretion did not decline despite a 63 per cent reduction in the plasma urate, it is likely that the reabsorption of filtered urate also was impaired by SKF-62698.     

Isolated defect in postsecretory reabsorption of uric acid.

A 26-year-old woman was found to have an abnormally sensitive excretory response to a rise in plasma urate with a markedly increased ratio of uric acid to creatinine clearance (exceeding 35%). Uric acid was studied before and after administration of pyrazinamide and benzbromarone. In the presence of pyrazinamide urinary uric acid decreased markedly just as in normal subjects. The uricosuric response to benzbromarone was reduced. No other renal tubular or metabolic abnormalities were found. It appears that the abnormality is related to an isolated defect in postsecretory reabsorption of urate.     

Effect of low dose daily aspirin on serum urate levels and urinary excretion in patients receiving probenecid for gouty arthritis

OBJECTIVE: To determine if low dose daily enteric coated aspirin significantly affects the therapeutic actions of probenecid with respect to serum urate levels or urinary urate excretion. METHODS: Patients with gouty arthritis taking a stable dose of probenecid for at least 3 months were enrolled in a prospective crossover study. Twenty-four hour urinary and serum uric acid levels were measured after 14 days in patients crossed over to receive probenecid alone; probenecid and aspirin 325 mg taken concomitantly; and probenecid followed by aspirin 325 mg at 6 hours. RESULTS: Eleven patients completed the crossover study. The addition of aspirin to a stable dose of probenecid had no significant effect upon serum urate levels or 24 h urinary urate excretion (p > 0.05, paired t test). CONCLUSION: Low dose daily enteric coated aspirin does not significantly interfere with the uricosuric effects of probenecid in patients with gouty arthritis.     

Sickel cell anemia, the nephrotic syndrome and hypoplastic crisis in a sibship

A family is presented with five siblings, three with sickle cell anemia and two with thalassemia trait. In all three children with sickle cell anemia hypoplastic crises developed after a viral infection. Two of these children were found to have the nephrotic syndrome, as did one of their siblings with thalassemia trait.Renal biopsy in the female patient with sickle cell anemia and the nephrotic syndrome revealed focal and segmental glomerulosclerosis. The biopsies of the other two patients (one with sickle cell anemia and one with thalassemia trait) revealed minimal changes. Hemosiderosis was present only in the biopsy specimens of the two patients with sickle cell anemia. All three patients were steroidresistant. Neither the other two siblings (one with sickle cell anemia and hypoplastic crisis) nor the parents have the nephrotic syndrome.The pathogenesis of nephrotic syndrome in patients with sickle cell anemia is discussed in detail. The current hypotheses relating renal disease to the sickling process are considered. The nephrotic syndrome observed in our patients appears to be familial and unrelated to sickle cell anemia, having been found in family members without, as well as with, sickle cell anemia. The findings in this family suggest that the nephrotic syndrome found in sickle cell anemia may not be causally related, but may be fortuitous, at least in some patients.     

Renal handling of urate in the syndrome of inappropriate secretion of antidiuretic hormone

Three patients with the syndrome of inappropriate secretion of antidiuretic hormone had elevated uric acid clearances. Their uric acid clearances decreased markedly after the administration of pyrazinamide. Probenecid was given to two of them and it produced large increases in uric acid clearance. These data suggest that enhanced secretion in the renal tubules was responsible for the increased clearance of uric acid. This article provides evidence that hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone is due to increased tubular urate secretion.     

Acute gout precipitated by total parenteral nutrition

Hypouricemia is seen in a variety of clinical situations. Although precipitation of gout is well known following initiation of uricosuric therapy, it has been reported rarely following the institution of total parenteral nutrition (TPN), despite its known uricosuric effect. We describe a patient who developed polyarticular gout on 2 occasions after a sudden decline in serum uric acid after initiation of purine-free TPN. Potential etiologies include increased urate clearance due to the infusion of glycine or amino acids. Monitoring of serum uric acid concentrations in patients with a history of gout may help predict a gout attack. Prophylactic treatment or alternative TPN formulations may be indicated.     

Fructose-induced hyperuricemia in essential hypertension

A rapid intravenous fructose load was given to nine normouricemic essential hypertensive and eight control subjects. The following increase in plasma uric acid concentration was significantly higher in hypertensives than in controls. There was no significant difference in urinary excretion of urate between the two groups. Since the increase in uric acid concentration brought about by fructose is most probably due to an increased metabolism of preformed purine nucleotides, it is suggested that essential hypertensive patients have a higher than normal “pool” of purine nucleotides.     

Effects of azelnidipine on uric acid metabolism in patients with essential hypertension

Purpose: To examine effects of a long-acting calcium channel blocker (CCB) azelnidipine on uric acid metabolism in hypertensive patients.

Methods: Azelnidipine was administered to 72 patients at a daily dose of 8?mg or 16?mg. In 22 cases out of the 72 patients, a different CCB was switched to azelnidipine. Blood pressure was measured and biochemical parameters of blood and urine were evaluated before and 2–3 months after the administration.

Results: Azelnidipine significantly decreased both systolic and diastolic blood pressure and the heart rate. It decreased both serum urate levels and the urinary uric acid to creatinine ratio (Uur/Ucr), but did not affect the uric acid clearance to creatinine clearance ratio (Cur/Ccr). Azelnidipine decreased both Uur/Ucr and Cur/Ccr in patients with Uur/Ucr ≥0.5 or ≥0.34, although it did not change these clearance parameters in patients with Uur/Ucr <0.5 or <0.34. Azelnidipine decreased the serum urate levels and Uur/Ucr in hyperuricemic patients with uric acid levels ≥7.0?mg/dL in males and ≥6.0?mg/dL in females. It did not change these parameters in normouricemic patients with serum urate levels <7.0?mg/dL in males and <6.0?mg/dL in females. Azelnidipine decreased Uur/Ucr and Cur/Ccr in hyperuricemic patients with normal or overexcretion of uric acid, although it did not change these clearance parameters in hyperuricemic patients with uric acid hypoexcretion.

Conclusions: Azelnidipine decreased the serum urate acid levels and Uur/Ucr, and this response was most prominent in hyperuricemic patients or patients with normal and overexcretion of uric acid.     

Hypouricaemia and increased renal urate clearance associated with hyperparathyroidism.

A 64-year-old female was found to have hypouricaemia, with serum uric acid ranging from 0.06-0.12 mmol/l (1.1-2.0 mg/100 ml), associated with an increased urate clearance of 48.9 ml/min and hyperparathyroidism. Known causes of increased uric acid clearance were excluded. Pyrazinamide reduced urate clearance dramatically to 2.1 ml/min, suggesting that the tubular defect was either one of increased secretion or a failure of postsecretory reabsorption. No other tubular abnormality was apparent except diminished urine concentrating ability. Hypouricaemia has not been previously reported in association with hyperparathyroidism and a mechanism relating the two disorders could not be readily postulated. The tubular defect shown in this instance resembled that reported in association with Wilson's disease and Hodgkin's disease. This case and earlier reports of isolated tubular defects of uric acid handling enhance our understanding of uric acid excretion.     

Sex differences in uric acid metabolism in adults: evidence for a lack of influence of estradiol-17 beta (E2) on the renal handling of urate

The serum urate concentration of adult women, which is lower than in men of a similar age, is thought to be related to a higher renal clearance of urate in women, possibly due to their higher plasma estrogen levels. Intersexual differences in the renal handling of uric acid was assessed in 9 normal adult women and 9 normal age-matched men. Women showed a significantly lower serum urate concentration as compared to men (3.5 +/- 0.3 v 4.9 +/- 0.7 mg/dL, P less than 0.001), higher fractional excretion of urate (9.8 +/- 1.0 v 7.3 +/- 0.8%, P less than 0.001), and significantly lower tubular urate postsecretory reabsorption (67.2 +/- 1.6 v 76.6 +/- 1.4% of secreted urate, P less than 0.01). To test whether plasma E2 has a uricosuric effect we administered estradiol valerate and estradiol benzoate to either oophorectomized or adult women. Plasma E2 levels and urinary total estrogen excretion increased significantly in both groups but the treatment failed to significantly modify serum urate or the fractional excretion of uric acid. Furthermore, in 4 normal adult women, the tubular phases that modulate the renal excretion of urate were not significantly influenced by increased plasma E2 levels. We conclude that in comparison to men of a similar age, the lower tubular urate postsecretory reabsorption of adult women is in accordance with the intersexual differences in uric acid metabolism. Plasma E2 does not influence renal handling of uric acid or serum urate levels.     

Renal handling of uric acid in normal and gouty subject: evidence for a 4-component system.

Bidirectional renal urate tranport was studied in both control and gouty subjects. 99.3% of filtered urate undergoes reabsorption as assessed by pyrazinamide suppression of urate secretion. The maximum uricosuric response to benzbromarone, equated with the minimum secretory rate, amounted to 50% of the filtered load in normal persons and was lower in gouty normoproducers. Since benzbromarone selectively inhibits reabsorption of secreted urate, the difference between secreted and excreted uric acid becomes a valid measure of urate reabsorption distal to the secretory site and amounts to 80% of the secreted load in both groups. These data conform to a 4-component model of renal urate handling in man.     

Pharmacokinetics and pharmacodynamics of different doses of Irtemazole in repeated application

Irtemazole, a new uricosuric substance, was tested in 12 normouricemic subjects in doses between 6.25-37.5 mg applied twice daily for 7 days per os. The plasma uric acid level decreased in all subjects, to a constant level within 1-2 days with application of the higher doses, and within 2-3 days with application of the lower doses, and was maintained as long as irtemazole was given. The average decrease of plasma uric acid was 20.4% at a dose of 6.25 mg irtemazole, 22.7% at 12.5 mg, 42.0% at 25 mg, and 45.7% at 37.5 mg. The renal uric acid excretion and the uric acid clearance increased to a constant level within 1 day of irtemazole application. The initial levels of plasma uric acid, uric acid excretion, and uric acid clearance were reached after 1-2 days after cessation of irtemazole. Within 1 to 2 days after ingestion of irtemazole a constant plasma irtemazole level and renal irtemazole excretion were observed in all doses throughout the application period. One to 2 days after discontinuation of irtemazole it was no longer detectable in plasma and urine. No side effects were found.     

Renal function in gout. V. Factors influencing the renal hemodynamics

Renal hemodynamics as measured by inulin clearance (Cinulin) and para-aminohippurate clearance (CPAH) was evaluated in 149 patients with primary gout over intervals of two to 22 years. In over 30 per cent of the patients plasma urate was greater than 10 mg/dl and urinary uric acid greater than 800 mg/min. A linear trend in decreasing frequency of hyperuricemia and excessive uricosuria is significantly related to the patient's age at the onset of gout. Group I consisted of 84 patients with uncomplicated gout in both clearance studies. Cinulin and CPAH were somewhat lower in patients larger than or equal to 50 years of age with longer duration of gout. Further reduction in clearances was minimal at the second clearance study in intervals of approximately 10 years. Group II included 27 patients who had no associated disease at the time of the first clearance study but in whom associated disease had developed by the time of the second clearance study. A striking reduction in Cinulin and CPAH was noted, especially in those 50 years old or above. There were 38 patients in group III with associated diseases at the time of both clearance studies. They had lower Cinulin and CPAH at the time of the first study, particularly the older patients. Further reduction during the second study was less striking than that in group II. Analyses of variance suggest that various coexisting vascular diseases with associated nephropathy have the most significant impact on the status of renal function in gout, with aging the second most important and duration of gout, the third.     

Uric acid excretion in healthy subjects: a nomogram to assess the mechanisms underlying purine metabolic disorders

The reference range for urinary uric acid excretion has not been precisely defined. Different urinary variables have been proposed to determine the renal contribution to increased or decreased serum urate concentrations. We examined which urinary variable best indicates uric acid excretion over a wide range of serum urate concentrations. Purine metabolism was studied in 10 healthy male subjects (aged 26-58 years) both at their endogenous normal serum urate levels (normouricemic state) and after the oral administration of allopurinol (300 mg/24 h for 5 days) and ribonucleic acid (4 g/8 h for 4 days) to decrease (hypouricemic state) and increase (hyperuricemic state) serum urate concentrations, respectively. The results from patients with several conditions known to affect uric acid synthesis and/or the renal excretion of uric acid were used to validate a constructed nomogram. Over a wide range of mean serum urate levels (from 2.7 to 9.5 mg/dL) and mean 24-hour urinary uric acid excretion (171 to 1368 mg/[24 h 1.73 m(2)]), the highest correlation coefficient between serum urate and uric acid excretion was obtained for the 24-hour uric acid determination (r = 0.928; P < .001). The constructed nomogram allowed the definition of the mechanism underlying hyperuricemia and hypouricemia in patients with a myriad of diseases known to affect purine metabolism. The urinary variable that best correlates with a wide range of serum urate concentrations is 24-hour urinary uric acid excretion. The constructed nomogram allows the identification of the kidney contribution to a given purine metabolic abnormality.     

Renal function and urate metabolism in late survivors with cyanotic congenital heart disease

Diminished glomerular filtration rate, proteinuria, and large hypercellular congested glomeruli with segmental sclerosis are found in late survivors with cyanotic congenital heart disease (CCHD). Hyperuricemia is common, acute gouty arthritis is less common than uric acid levels would predict, and overt tophaceous deposits of uric acid are exceptional. The role of the kidney in causing the basic biochemical disturbances, and the relative importance of impaired urate excretion vs urate overproduction have not been established. Accordingly, we reviewed the courses of two index patients and prospectively studied eight additional CCHD patients from 28 years to 46 years old with mean hematocrits of (62 +/- 10%). Plasma creatinine concentration was normal (0.9 +/- 0.1 mg/dl) yet glomerular filtration rate was mildly reduced to 93 +/- 14 ml/min as measured by creatinine clearance and to 81 +/- 6 ml/min as measured by 111In DTPA. Three patients had significant proteinuria and one was nephrotic. Plasma uric acid concentration was high in all but one (8.2 +/- 2.1 mg/dl), mean 24 hr uric acid excretion was normal (564 +/- 221 mg), and fractional uric acid excretion was relatively low (6.3 +/- 2.6%). The two patients with highest plasma uric acid levels (12.0 and 10.2 mg/dl) had the lowest fractional excretions (2.8% and 4.0%). Both of these patients had diminished capacity to excrete a water load (38% and 27%/4 hr) and to maximally concentrate urine (520 and 635 mOsm/kg after water deprivation and vasopressin). In conclusion, high plasma uric acid levels in late survivors with CCHD are secondary to inappropriately low fractional uric acid excretion, not to urate overproduction.(ABSTRACT TRUNCATED AT 250 WORDS)