T'sai Fan Yü

Renal function in gout: With a commentary on the renal regulation of urate excretion, and the role of the kidney in the pathogenesis of gout

Abstract 1.1. A study was made of renal function in some 300 gouty subjects. Standard renal clearance technics were employed in approximately 160 cases, including some asymptomatic hyperuricemic relatives of these gouty subjects. 2.2. C inulin , C PAH and Tm PAH were for the most part consonant with the values found in normal subjects of equivalent age, but impairment of renal hemodynamics was not infrequent particularly in those of advanced age or with overt renal disease. 3.3. Determinations of urinary urate excretion, whether measured as UV urate in short clearance experiments or in twenty-four-hour urine collections, gave values within the normal range in most cases. In a significant minority of instances, however, the urinary urate excretion was unequivocally in excess of the limits of normal variation. 4.4. The filtered urate load was found to be increased in most gouty subjects. The presumptive tubular reabsorption of urate was correspondingly increased but, so far as could be determined, not disproportionately so in relation to the percentage of urate reabsorbed by the tubules at equivalent filtered urate loads in normal man. 5.5. The results thus indicate essentially normal discrete renal functions in most gouty subjects. With advancing years and disease, however, the glomerular filtration rate progressively declines and some tubules apparently deteriorate. Secondary renal retention of urate then becomes apparent. 6.6. The data fail to disclose any primary defect in tubular function, specifically of abnormally enhanced tubular reabsorption of urate. On the contrary, the clearance data imply overproduction of urate in gout. This interpretation is supported by reference to metabolic data. 7.7. The question of tubular excretion of urate is reviewed. The available clearance data are not incompatible with the view that the filtered urate load, assuming complete filtrability of plasma urate, normally is wholly or in very large part reabsorbed by the tubules, and that the excreted urate derives entirely, or for the greater part, from tubular secretion; the analogy with potassium excretion is pointed out. Indirect but not direct support of this postulation is presented. 8.8. It is concluded that the pathogenesis of hyperuricemia and of the other manifestations of gout cannot be ascribed to any hypothetic primary renal defect, whether of abnormally great tubular reabsorption or deficient tubular secretion of urate.

STUDY OF THE PARADOXICAL EFFECTS OF SALICYLATE IN LOW, INTERMEDIATE AND HIGH DOSAGE ON THE RENAL MECHANISMS FOR EXCRETION OF URATE IN MAN *

of a salicylate metabolite, gentisic acid. The re- lationships between the renal excretion of salicyl- ate and of urate are then examined by means of simultaneous clearance techniques, including studies under conditions of urine pH made to vary from markedly acid to markedly alkaline. Clearance data on the antagonistic effect of small doses of salicylate on probenecid uricosuria, and vice versa, also are presented. Finally, the im- plications of the results as a whole are considered in relation to current concepts of renal mecha- nisms for the excretion of salicylate and of urate, with special reference to inferences regarding the possibility of tubular excretion of urate in man.

Tubular secretion of urate in man.

In normal man, the renal clearance of urate is only a small fraction, some 5 to 10 per cent, of the inulin clearance. The prevailing interpretation of this low urate/inulin clearance ratio assumes complete filtrability of the plasma urate at the glomerulus, an assumption supported by several lines of evidence (1-7); reabsorption of 90 to 95 per cent of the filtered urate; and excretion of that 5 to 10 per cent which has escaped reabsorption. The renal regulation of urate excretion in man is thus considered to be limited to the processes of glomerular filtration and tubular reabsorption. There are some difficulties with this concept. Berliner, Hilton, Yu and Kennedy (2), in demonstrating a Tm urate for normal man of the order of 15 mg. per minute, pointed out that this reabsorptive rapacity is far greater than any filtered urate load normally imposed upon it. Consequently, the Tm for urate cannot be considered directly to determine the quantity of urate excreted, which is regulated by a proximate mechanism as yet undefined. Not easily reconciled with the current concept is the striking dissociation between filtered urate loads and excreted urate noted over a wide range of glomerular filtration rate in clearance studies of 150 gouty subjects (8). Further, the marked suppression of renal excretion of urate in man after administration of pyrazinamide (9) or lactate (10) would, in the conventional view, require the rather awkward assumption that tubular reabsorption of urate is stimulated by these compounds. Finally, the paradoxical effect of salicylate and other drugs on urate excretion in man (11) would, according to the conventional concept, necessitate the presumption that small doses stimulate, and large doses of the same drug suppressl tubular reabsorption of

Effect of sodium lactate infusion on urate clearance in man.

Summary Renal clearance studies are described which corroborate and extend earlier observations indicating that administration of sodium lactate in sufficient dosage results in a profound fall in urinary excretion of uric acid. Curate declined from a mean control level of 10.4 ml/min. to a mean minimum of 1.4 ml/min. The uricosuria produced by salicylate and probenecid was temporarily abolished by lactate. The significance of these findings is discussed.

Effect of pyrazinamide and pyrazinoic acid on urate clearance and other discrete renal functions.

Summary 1. The effect of pyrazinamide and pyrazinoic acid on the renal clearance of urate, inulin and p-aminohippurate, in some instances also TmPAH, was studied in 10 human subjects. 2. A rapid and marked reduction in urate clearance was noted, without decrease in the filtered urate load. The implications as to the renal mechanisms regulating urate excretion are discussed. 3. Data indicating that the effect of pyrazinamide is ascribable largely to the action of pyrazinoic acid are presented.

Suppression of tubular secretion of urate by pyrazinamide in the dog.

Summary Pyrazinamide depresses Curate/GFR in the Dalmatian and non-Dalmatian dog. Stop-flow studies revealed unequivocal suppression of tubular secretion of urate in the Dalmatian and gave no indication of enhancement of tubular reabsorption of urate in the non-Dalmatian.

A simultaneous study of glycine-N15 incorporation into uric acid and heme, and of Fe59 utilization, in a case of gout associated with polycythemia secondary to congenital heart disease

Abstract By simultaneous use of glycine-N 15 and Fe 59 as tracers the interrelationships between purine, porphyrin and iron metabolism were studied in a patient with gout associated with polycythemia secondary to congenital heart disease. The time course of glycine-N 15 incorporation into uric acid was unlike that previously observed in normal subjects and in patients with primary gout, in whom peak enrichment of uric acid N 15 occurs within two to four days of administration of the isotope. In the case recorded herein there was progressive increase in the N 15 abundance of the urinary uric acid until the tenth day. The protracted uric acid biosynthesis observed in this instance of secondary gout is presumed to reflect the augmented turnover of red cell precursor nucleic acids associated with increased erythropoiesis characterizing the polycythemic state. The time course of glycine-N 15 incorporation into heme in this case of secondary polycythemia did not deviate significantly from the normal, thus corresponding with the similar findings reported in polycythemia vera. As in other recorded instances of increased crythropoietic activity due to primary and secondary polycythemia, the initial half-time of disappearance of injected Fe 59 from the blood plasma was reduced (in this case to thirty-one minutes), the rate of Fe 59 incorporation into circulating red cells was correspondingly accelerated and the utilization of the Fe 59 for erythrogenesis was increased, by the seventh day, to over 90 per cent of the amount injected. The turnover rate of Fe 59 was accelerated both in the plasma and in the red cells.

The effect of the interaction of pyrazinamide and probenecid on urinary uric acid excretion in man.

Complex interactions occur between pyrazinamide (PZA) and probenecid in man involving both the metabolism and distribution of the drugs, and their effects on renal tubules. Pretreatment with PZA prolonged the half-life (T 1/2) of probenecid without changing its plasma-binding. As the rate of probenecid metabolism is decreased, its uricosuric action tends to be prolonged and the effect of PZA lessened. The PZA-suppressible urate level is increased to values well above control after the administration of probenecid; it is less after alkalinization of urine, although still larger than the value for PZA-suppressible urate after the administration of PZA alone. Urinary probenecid excretion is much greater when urine is alkalinized. These observed drug interactions, plus the known effect of probenecid to block secretion of PZA, have to be considered in evaluating the effect of the two drugs given together, compared to the effect of each drug given separately.

Effect of Reducing Renal Arterial Blood Pressure by Balloon Catheter on Urate Excretion in the Dog.

Summary Reduction of mean renal arterial blood pressure of Dalmatian and mongrel dogs by inflating a balloon-tipped catheter inserted into the aorta just above the renal arteries resulted in a proportionate decrease in GFR, less decrease in CPAH, a precipitous fall in UNaV/FNa, no appreciable change in UKV/FK. In the Dalmatian, under conditions of net secretion of urate, UurateV/Furate was unchanged or rose somewhat. A comparable response of UurateV/Furate was obtained in mongrels under conditions of net reabsorption of urate, a result consistent with tubular secretion of urate masked by preponderant tubular reabsorption.