Uric Acid Clearance Research Articles

Renal excretion of uric acid during prolonged fasting

Serum and urine uric acid were evaluated during prolonged therapeutic fasting in 15 obese patients. With increasing ketonemia the serum uric acid rose from a control value of 5.9 ± 0.4 to 12.5 ± 1.0 mg 100 ml at 7 days and then decreased progressively to 7.7 ± 1.3 mg 100 ml by 28 days despite sustained ketonemia. The uric acid clearances were 5.5 ± 0.9, 1.8 ± 0.2, and 4.4 ± 1.5 ml/min at days 0, 7, and 28 of fasting. At the same times the creatinine clearances were 114 ± 11, 80 ± 6, and 64 ± 6.3 ml/min. There was no evidence of a renal tubular abnormality as assessed by glycosuria, bicarbonaturia, or increased phosphaturia. Urate binding to plasma proteins remained unchanged. Acute studies of the renal handling of uric acid revealed a uricosuric response to the administration of sodium lactate or sodium bicarbonate by intravenous infusion and low-dose acetylsalicylic acid orally. This renal tubular response departs significantly from that observed during the overnight fasted state and could not be accounted for by extracellular fluid volume expansion or the induced acid-base changes.

Ascorbic acid-induced uricosuria. A consequency of megavitamin therapy.

The effect of ascorbic acid on the serum and urinary uric acid was studied in 14 subjects. Two to 6 h after the ingestion of 4.0 g of ascorbic acid, the fractional clearance of uric acid increased to 202% +/- 41% of the control value. This uricosuria was inhibited by pyrazinamide and by low-dose acetylsalicylic acid, but was not accompanied by an increase of the creatinine clearnace. Ascorbic acid did not diminish protein-bound uric acid. In 3 subjects who ingested 8.0 g of ascorbic acid for 3 to 7 days the serum uric acid decreased by 1.2 to 3.1 mg/dl as a result of a sustained uricosuria. These results suggest that ascorbic acid could invalidate studies involving the measurement of uric acid and obscure the diagnosis of gout in some cases. Theoretically it could precipitate attacks of gouty arthritis or renal calculi in predisposed persons. These observations show a pharmacologic effect of megadoses of a simple vitamin.

Renal function before and after unilateral ephrectomy in renal donors

Measurements of glomerular filtration rate (GFR), effective renal plasma flow (ERPF), tubular maximum reabsorption of glucose (Tmglucose) and secretion of para-aminohippurate (Tmpah), clearance of inorganic phosphate (Cphosphate) and uric acid (Curic acid), urine diluting capacity (CH2O) and urinary net acid excretion (UH + V) were made before and 10 to 14 days after unilateral nephrectomy in seven healthy renal donors. Comparisons were made between the functions of the remaining kidney and 50% of pre-uninephrectomy values. Mean post-uninephrectomy GFR increased by 36%, and mean ERPF, 55%. Tmglucose, Tmpah, Cphosphate, uric acid, CH2O, UH + V increased significantly, after uninephrectomy. The increase in Tmpah, Tmglucose and CH2O is proportional to the rise in GFR while the increase in Cphosphate, Curic acid and UH + V is proportionally greater than the increase in GFR. The changes in post-uninephrectomy renal handling of phosphate are not due to an increase in parathyroid hormone secretion.

Gout as a complication of Bartter's syndrome. A possible role for alkalosis in the decreased clearance of uric acid.

A prevalence of hyperuricemia of 50% and of acute gouty arthritis of 20% has been observed in a group of patients with Bartter's syndrome. All patients except one presented initially with complaints unrelated to uric acid metabolism. The cause of their hyperuricemia and subnormal clearance of uric acid is unexplained. Systemic alkalosis, a prominent feature of Bartter's syndrome, can decrease the clearance of uric acid and may contribute to the hyperuricemia and gout that have been observed. Physicians should be aware of the possibility of gout as a clinical complication of Bartter's syndrome and of the inhibitory effects of alkalosis on urate clearance.

Renal Tubular Dysfunction and Cirrhosis

To the Editor. —The recently published study by Michelis et al1demonstrates a defect in tubular reabsorption of uric acid in patients with cirrhosis, and the authors suggest this relates to hyperbilirubinemia. However, patients with liver disease frequently have metabolic alterations other than hyperbilirubinemia that may cause renal tubular dysfunction. Tubular transport of solutes such as uric acid may be linked with sodium transport and changes in extracellular fluid volume may alter tubular reabsorption of many solutes, including sodium and uric acid, in a relatively nonspecific manner.2Disorders associated with a contracted extracellular fluid volume (diabetes insipidus, salt restriction, vigorous diuretic therapy) may be associated with increased proximal tubular sodium reabsorption and decreased uric acid clearance. Conversely, situations in which there is expansion of the extracellular fluid volume (saline loading, excessive circulating antidiuretic hormone, diuretic use with salt replacement) have been associated with hypouricemia and increased excretion

The influence of the extracellular fluid volume on the tubular reabsorption of uric acid.

Changes is tubular reabsorption of uric acid in response to alterations in the extracellular fluid volume (ECFV) were examined in rats by clearance studies and by direct intratubular microinjections. Contraction of the ECFV led to a rise in the serum uric acid concentration and a 47% decrease in the clearance of uric acid. The ratio of uric acid to inulin clearance also fell, indicating an increase in the net tubular reabsorption of urate. Volume expansion resulted in an increase in the urate clearance and a 37% decrease in the net tubular reabsorption of uric acid. To localize the site in the nephron where these changes occur, microinjections of [2-14C]urate were performed. The lack of conversion of radioactive urate to allantoin after microinjections was demonstrated by thin-layer chromatography. After contraction of the ECFV, urinary recoveries of uric acid were significantly decreased after microinjections into proximal tubular sites. In contrast, recoveries were increased from these proximal sites after volume expansion. No evidence for distral reabsorption was obtained in any group of animals. These studies demonstrate that net urate reabsorption is influenced by the state of hydration of the ECFV and that these alterations are mediated by changes in the rates of reabsorption in the proximal tubule.

A model for evening home hemodialysis

In an effort to better rehabilitate patients on home dialysis by shortening the duration of effective dialysis and thereby permitting evening hemodialysis, the simultaneous use of two hollow fiber artificial kidneys (HFAK) was evaluated. The clearances of urea, creatinine, uric acid, phosphate, iothalamate and cyanocobalamin were substantially higher than those obtained with any available single dialyzer. These clearances also were significantly enhanced by use of the single pass dialysate delivery system as compared to the recirculating single pass system. The clearances were comparable whether the blood flow through the two HFAK was in parallel or in series. Reuse of the HFAK was feasible, thus minimizing any economic disadvantage of the system. In eight patients, who have used the system at home for 9 to 12 hours per week for up to 6 months, weight, blood pressure, serum chemistries and motor nerve conduction have remained stable. This shorter dialysis with the double HFAK system allows for evening dialysis, thus freeing daytime hours for productive activity and nighttime for sleep.

Proceedings: Cyclophosphamide and the kidney.

The effect of cyclophosphamide on renal function was studied in 17 normally hydrated patients with cancer. No nephrotoxic effects were observed. High-dose cyclophosphamide (⩾50 mg/kg body weight) did, however, impair water excretion as manifested by weight gain, hyponatremia, and inappropriately concentrated urine. The decrease in serum osmolarity (range 6-41mOsm/L) and increase in urine osmolarity (range 305–798 mOsm/L) occurred 4–12 hours after cyclophosphamide administration, lasted 20–24 hours, and correlated temporally with the urinary excretion of cyclophosphamide alkylating metabolites. In three patients who demonstrated the water retention syndrome plasma vasopressin concentration was determined; in only one could the rise in urine osmolarity be explained by a concomitant increase in circulating vasopressin levels. No change in creatinine clearance or urinary excretion of protein, sodium, potassium, calcium, phosphorus, uric acid, and amino acids was observed after cyclophosphamide. Two patients (9%) developed hemorrhagic cystitis; no other abnormalities of urine sediment occurred.

Urate excretion and urine flow in a lithium-induced diabetes insipidus rat model.

The relationship of urine flow to the excretion and clearance of uric acid was studied in rats at their normal endogenous plasma urate concentrations during saline infusion, utilizing a lithium-induced diabetes insipidus model. Thirteen rats were pretreated with intraperitoneal lithium for 4–7 days, while six control animals received intraperitoneal sodium. Six of the lithium-treated rats developed diabetes insipidus, while the other seven (which received less lithium, but developed similar plasma lithium concentrations) did not. Although urine flow more than tripled in the rats with diabetes insipidus, urate excretions and clearances were similar in the diabetes insipidus rats, the lithium-treated rats without diabetes insipidus, and the sodium-injected controls. No relationship between urine flow and renal urate elimination in the rat could be discerned in these studied despite great variations in flow within terminal portions of distal nephrons. It is suggested that many physiologic and pharmacologic variables may affect urine flow and urate elimination in the rat concomitantly, but independently.

Is uric acid transported by the hippurate transport system?

Experiments were designed to determine whether renal excretion of uric acid is achieved by the same mechanism as for renal tubular excretion of hippurates and related organic acids. Surviving slices of rabbit kidney cortex were unable to accumulate C14-urate by a concentrative mechanism. Further, entry of C14-urate into renal slices was unaffected by acetate, probenecid or anoxia in accord with earlier observations from this laboratory with non-radioactive urate. Experience with isolated perfused rat liver supports the use of this experimental method as a model of the hippurate transport system. Unlike hippurate and a large number of related organic anions, neither urate nor C14-activity derived from urate was concentrated in the bile from this preparation. Probenecid did not inhibit excretion of the small amounts of C14-activity which did appear in the bile. Urate did not compete with indigo carmine, a nonmetabolizable substrate of the hippurate transport system, for excretion into the bile. From these findings, it is concluded that urate and organic acids such as hippurate do not behave similarly in kidney or in liver. The possibility that urate might be excreted by an independent active transport mechanism is not excluded. The demonstration that renal tissues can synthesize urate from hypoxanthine raises the possibility that urate synthesis might also occur in the intact animal and might contribute to the renal clearance of uric acid.

The sites of action of bumetanide in man

Some pharmacological effects of bumetanide were investigated in 8 healthy volunteers. It was a very potent diuretic, as judged by the fact that, at peak effects during water diuresis, 20% of filtered sodium was excreted in the urine. During water diuresis it reduced free water clearance by approximately 25% and during hydropoenia it reduced the reabsorption of solute free water to a similar extent, indicating a major site of action on the ascending limb of the loop of Henle. A significant phosphaturia was induced during the period of maximum diuresis suggesting an additional action on the proximal tubule. The excretion of urinary titratable acid and ammonium as well as potassium were increased, indicating that the drug did not have a significant effect on sodium transport in the distal tubule. Glomerular filtration rate was not affected but the drug caused a decrease in the renal clearance of uric acid.

Renal uric acid excretion in patients with chronic pyelonephritis.

In 25 patients in different stages of chronic pyelonephritis the renal clearance of uric acid, osmotically active substances and endogenous creatinine and their mutual relationship were investigated. It was found that the ratioCua/Ccr×100 rises in a hyperbolic relation with the decline of endogenous creatinine clearance. The rise of the ratioCua/Ccr×100 rose in a linear relationship to the fractional excretion of all osmotically active substances (Cosm/Ccr×100). The findings support the idea that osmotic diuresis in the residual nephron is one of the factors conditioning the relative increase of renal uric acid excretion.

Effect of oestrogen therapy on plasma and urinary levels of uric acid.

Uric acid clearance studies were carried out on a low-purine diet in 22 trans-sexual men before and during oestrogen therapy for this condition (stilboestrol in 21 cases, ethinyloestradiol in one). Plasma uric acid fell in 15 of the subjects and urinary uric acid rose in 17 of 20 subjects in whom satisfactory collections were obtained. These changes are significant and it is suggested that hormonal influences are responsible for the known age and sex differences in plasma uric acid.

Evaluation of renal function following double dose infusion intravenous cholangiography.

EVALUATION OF RENAL FUNCTION FOLLOWING DOUBLE DOSE INFUSION INTRAVENOUS CHOLANGIOGRAPHYE. NICHOLAS SARGENT, M.D., BENJAMIN H. BARBOUR, M.D., NIVIA ESPINOSA, M.D. and HARVEY I. MEYERS, M.D.Audio Available | Share

Moderate sodium restriction and diuretics in the treatment of hypertension

Using a cross-over type setup with 4 periods of 1 month each in 22 patients with mild, mostly essential hypertension, the antihypertensive action of the following therapeutic regimens were compared: (1) a regular diet and placebo (period RP), (2) a regular diet and 100 mg. hydrochlorothiazide and 100 mg. spironolactone (period RD), (3) a moderate sodium restriction and placebo (LP period), and (4) this diet together with the same diuretics (period LD). The diuretics or placebo were administered on a double blind basis, while the sodium restriction or regular sodium diet was prescribed in an open, but randomized system. The 24 hour urinary sodium averaged 191.1 ± 61.2 mEq. during the RP period and 92.8 ± 41.8 mEq. during the LP period. Compared to the RP period, the reduction in home blood pressures was more important with diuretics alone ( 16.1 8.1 mm. Hg) than with this moderate sodium restriction alone ( 7.7 4.4 mm. Hg), while the combination of both produced a statistically significantly (p < 0.005) higher blood pressure reduction ( 20.7 10.8 mm. Hg). Not only the diuretics but also the sodium restriction increased the serum uric acid, and this could be related to the decreased urinary uric acid clearance. A significant (p < 0.001) correlation (r = 0.66) was obtained between the decrease in systolic blood pressure (expressed in mm. Hg) produced by the sodium restriction (y) and the decrease in 24 hour urinary sodium excretion (expressed in mEq.) produced by the same diet: y=−6.58+0.163 x These data suggest that a reduction of the daily NaCl intake from 10 to 5 Gm. could produce a decrease of blood pressure of about 10 5 mm. Hg.

Hexose infusions in Cebus monkeys: Effects on uric acid metabolism

High dosage, sustained infusions of glucose, galactose, mannose, and fructose were performed in the New World monkey Cebus albifrons. Infusion of fructose led to a rapid increase in plasma and urine uric acid in each experiment with subsequent return toward base-line values despite further increases in fructose concentration. Concurrent isotopic studies of uric acid turnover showed a prompt increase in uric acid pool size during fructose infusions in two monkeys. These data are consistent with accelerated catabolism of a limited pool of preformed purines. The other three hexoses studied also lead to increased uric acid excretion with smaller increases in plasma concentration, although the mechanism of this increase is less clear. In one turnover study, no effect of glucose infusion on uric acid pool size was detected. All four hexoses led to a prompt increase in uric acid clearance. This early rise, however, was not sustained despite progressively increasing glycosuria.

Uric acid in advanced renal failure.

1. The results of studies of renal uric acid excretion in eleven patients with advanced chronic renal failure are presented. 2. The pyrazinamide suppression test was used to separate secretion from reabsorption of uric acid in the renal tubule. 3. There is a marked increase in the excretion and clearance of uric acid as renal function deteriorates. This was due to a striking increase in tubular secretion of urate and to incomplete reabsorption of filtered urate. 4. The remarkable functional capacity of the remaining nephrons of the chronically diseased kidney with respect to uric acid transport might be due to a uricosuric factor in uraemic serum.

Hypouricemia due to isolated renal tubular defect: Dalmatian dog mutation in man

A twenty-three year old man was found to have low serum urate concentrations (0.9 to 1.8 mg/100 ml) during evaluation for recurrent urinary calcium oxalate stones. His urinary clearance of uric acid was markedly increased (30 to 46 ml/minute), and was only minimally decreased after administration of pyrazinamide, an inhibitor of renal tubular secretion of uric acid. No other renal tubular abnormalities were detected. His sister also was hypouricemic and had an increased renal clearance of uric acid. We suggest that this man had a genetically determined renal abnormality affecting tubular reabsorption of uric acid; a similar defect is present in the Dalmatian coachhound. The association of idiopathic hypercalciuria with the renal uric acid reabsorptive defect in this case is probably fortuitous.

Impaired renal clearance of uric acid in chickens having hyperuricemia and articular gout.

Impaired renal clearance of uric acid in chickens having hyperuricemia and articular gout.

Nephrotoxicity of amphotericin B, with emphasis on changes in tubular function

Eight patients were treated with amphotericin B; all showed at some time a pronounced fall in glomerular filtration rate and renal blood flow with a variable change in filtration fraction. The maximal decrease was not dose related. The most consistent change in proximal tubular function was an increase in the clearance of uric acid which rose with increasing dosage of amphotericin B and varied inversely with the glomerular filtration rate. The major changes in distal tubular functions were (1) increased clearance of potassium as the dose of amphotericin B increased and glomerular filtration rate fell; (2) development of renal tubular acidosis in five of six patients, the primary change being decrease in titratable acidity; and (3) in the absence of an acid load, a rise in urine pH or fall in hydrogen ion excretion tended to precede a significant fall in glomerular filtration rate. To detect this we stress the use of an acid-ash diet and daily determination of urine pH.