Lawrence Berger

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.

Renal function in gout: IV. An analysis of 524 gouty subjects including long-term follow-up studies

Renal function studies were performed in 524 gouty subjects, including follow-up studies at intervals up to 12 years in 112 of them. In 49 subjects, the glomerular filtration rate was less than 70 ml/min and Curate:glomerular filtration rate ratio tended to rise as the glomerular filtration rate decreased, reflecting a relatively stable urate excretion over varying filtered urate loads. The increment in Tsurate:glomerular filtration rate was small with spontaneous Purate between 7 and 9 mg/100 ml. It was modest with Purate up to 10 mg/100 ml. The increment in Tsurate:glomerular filtration rate became much higher beyond Purate of 10 mg/100 ml. Urinary urate levels above 800 mug/min, designated as excess urate excretion, occurred more commonly in subjects with Purate above 9 mg/100 ml, and with better preserved renal function. Tophi were more frequently observed in subjects with low glomerular filtration rate and proteinuria; but incidence of urolithiasis seemed to be less affected by a decrease in the glomerular filtration rate. Hyperuricemia alone had no deleterious effect on renal function as evidenced by follow-up studies over periods up to 12 years. Deterioration of renal function was largely associated with aging, renal vascular disease, renal calculi with pyelonephritis or independently occurring nephropathy. In only very few instances was diminished renal function ascribable to gout alone.

Impaired renal function in gout: Its association with hypertensive vascular disease and intrinsic renal disease

Inulin clearance was measured in 624 patients with gout, and para-aminohippuric acid (PAH) clearance in 359; Group I consisted of 397 patients with uncomplicated gout; Group II, 191 patients with hypertension and/or ischemic heart disease; and Group III, 36 patients with chronic renal disease. Mean inulin clearance was normal in Group I, slightly depressed in Group II and more markedly decreased in Group III. There was some reduction in PAH clearance in all groups, but not in the very young patients with no complications. A disproportionate reduction in PAH clearance was noted in Groups II and III, particularly in the older patients with longer duration of gout. Uncomplicated gout, except in rare cases of fulminating gout, does not lead to decreased renal hemodynamics. An increased incidence of tophi correlates with decreased renal function, but incidence of renal calculi does not. Renal insufficiency when seen in patients with gout usually correlates with coexistence of hypertension, ischemic heart disease, or primary preexistent renal insufficiency.

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.

Renal function in gout: II. Effect of uric acid loading on renal excretion of uric acid

Abstract Thirteen non-gouty and twelve gouty men to whose regular diet was added 4 gm. of ribonucleic acid (RNA) daily, developed increases in plasma uric acid, urinary excretion of uric acid and derived parameters, without significant differences in the mean increments in non-gouty and gouty subjects. Ten non-gouty and seventeen gouty men were given intravenous injections of 1.1 to 2.5 gm. uric acid to impose even greater demands upon the tubular mechanisms for transfer of uric acid, and again the mean increments in the urinary excretion of uric acid and uric acid clearance in non-gouty and gouty subjects were indistinguishable. Pyrazinoic acid, a potent inhibitor of tubular secretion of uric acid, was found to suppress the urinary elimination of rapidly infused uric acid in gouty and non-gouty subjects alike. The data indicate that gouty subjects can excrete large extraneous loads of uric acid with as much facility as normal man, and support the view that this obtains also for the usually smaller and more slowly delivered endogenous uric acid loads natural to gout. The results thus argue against any intrinsic defect, peculiar to gout, in the renal mechanisms for excretion of uric acid. Briefly reviewed is the evidence that tubular secretion of uric acid occurs in non-gouty and gouty man, indeed that virtually all the uric acid appearing in the urine ordinarily derives from tubular secretion, hence virtually all the filtered uric acid ordinarily must be reabsorbed. It is pointed out that in this version of the filtration-reabsorption-secretion hypothesis there need be no simple relationship between the filtered and excreted uric acid, a dissociation found in gout that has been interpreted by others as indicating a primary tubular defect in transfer of uric acid. The implications of the filtration-reabsorption-secretion hypothesis in respect to other aspects of the renal regulation of uric acid are discussed in relation to excretion of uric acid in normal and gouty man under natural and artificial conditions of uric acid loading. The present study, limited to over-all clearances, gives no information as to the precise mechanisms or quantitative aspects of tubular secretion of uric acid in normal or gouty man, nor does it explain just how renal excretion of large and rapidly imposed uric acid loads is regulated.

Renal function in gout: III. Estimation of tubular secretion and reabsorption of uric acid by use of pyrazinamide (pyrazinoic acid)

Abstract Renal clearance was measured in ten patients with primary gout and five normal men before and after the administration of pyrazinamide or pyrazinoic acid to suppress tubular secretion of uric acid, thus permitting separate estimations of tubular influx and efflux of uric acid. In both gouty and nongouty subjects tubular reabsorption of the filtered urate was found to be virtually complete, the excreted uric acid deriving almost entirely from tubular secretion. No significant correlation could be made between plasma urate concentration and rate of tubular secretion of urate in normal persons in the steady state with P ur 3 to 7 mg. per cent, or in gouty subjects with P ur increased to about 9 mg. per cent; however, tubular secretion of urate was increased in gouty subjects with P ur > 9 mg. per cent (gouty overexcretors of uric acid). Allopurinol given to gouty subjects for short-term periods decreased the renal clearance of uric acid due to a disproportionate decline in tubular secretion of uric acid; conversely, feeding of RNA had the reverse effects, in both instances corresponding qualitatively and quantitatively to the changes in normal man similarly treated by Steele and Rieselbach. On the basis of the available evidence, it is concluded that the pattern of renal regulation of uric acid excretion in primary gout corresponds to that in normal man, and that it is not necessary to postulate a specific renal defect in elimination of uric acid.

The effect of ascorbic acid on uric acid excretion with a commentary on the renal handling of ascorbic acid

Under spontaneous conditions in man and dog, very little ascorbic acid is excreted in urine. Ascorbic acid clearance (C ascorbic acid) is promptly augmented when plasma ascorbic acid is increased by intravenous injection. No net tubular secretion of ascorbic acid is demonstrable in either man or dog when plasma ascorbic acid is elevated to levels as high as 12 mg/100 ml in man, and 28 mg/100 ml in the dog. Nevertheless, both in men and the Dalmatian dog, when the glomerular filtration rate (GFR) is decreased, excreted ascorbic acid in relation to the amount filtered is exaggerated so that C ascorbic acid:GFR approaches unity. It is possible that secreted ascorbic acid is masked under ordinary circumstances, with a more significant contribution of secreted ascorbic acid to total urinary ascorbic acid becoming apparent under conditions of low GFR. In man, when the plasma ascorbic acid level is raised to above 6 mg/100 ml, C urate:GFR rises from control value of 0.081 +/- 0.020, to 0.116 +/- 0.026. In both mongrel and Dalmatian dogs an effect of ascorbic acid on urate excretion is not conclusively shown. The uricosuric effect of ascorbic acid in man may be due to competition with uric acid for renal tubular reabsorptive transport. The difference in the metabolism of ascorbic acid in the dog as compared to man may help account for the inconsistent effect of ascorbic acid on uric acid excretion in the dog.

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 patients 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.

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.