Ts'ai-Fan Yü

Uric Acid Nephrolithiasis

Abstract Available estimates indicate that about 10 per cent of all renal calculi encountered in the U.S.A. as a whole are composed of uric acid and that the prevalence of uric acid nephrolithiasis in the population at large is of the order of 0.01 per cent. In pathogenesis the critical factors are those that lead to supersaturation of the urine with respect to undissociated (free) uric acid, which is more sparingly soluble than urates, and the factors that lead to separation of solid phase uric acid from its saturated solution in the urine, with organized crystal overgrowth. In regard to the first, the importance of persistent undue acidity of the urine, hyperuricosuria and contraction of the urine volume is stressed; the controversial role of deficient urinary ammonium excretion in undue acidity of the urine is discussed. In regard to the second, it is concluded that initiating uric acid crystals probably form the nidus in most cases, seeds of calcium oxalates in some. An etiologic classification of uric acid nephrolithiasis is proposed and the various categories discussed: idiopathic uric acid nephrolithiasis; uric acid stones associated with inborn errors of metabolism, neoplastic disorders and hyperuricemia of undetermined cause; with dehydration; and with hyperuricosuria without hyperuricemia. Conventional medical management is reviewed. The beneficial effects of supplementary treatment with allopurinol in 108 difficult cases of uric acid nephrolithiasis are summarized, with illustrative case reports.

Renal clearance of oxipurinol, the chief metabolite of allopurinol

Abstract Oxipurinol (4,6-dihydroxypyrazolo(3,4-d)pyrimidine; alloxanthine) is the chief metabolite of allopurinol in vivo . Like allopurinol, although to a lesser degree, oxipurinol suppresses xanthine oxidase and lowers the serum and urinary uric acid levels; indeed, for reasons indicated, much of the effect of allopurinol may well be due to oxipurinol. Unlike allopurinol, but like uric acid, oxipurinol appears to be reabsorbed by the tubules, since its renal clearance is much less than the glomerular filtration rate in man and the mongrel dog, although it is not bound to plasma proteins. Moreover, uricosuric drugs increase the clearance of oxipurinol in man, but not in the Dalmatian dog. Oxipurinol apparently is not secreted by the tubules. In the presence of marked kidney damage the renal clearance of oxipurinol is impaired and the plasma oxipurinol concentration in patients given usual allopurinol dosages is elevated. Patients with marked renal insufficiency appear to exhibit a higher incidence of side reactions than do patients with normal renal function.

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.

An abnormality of glutamine metabolism in primary gout

Abstract Six gouty and four nongouty men were given a standard oral dose of glycine-N 15 , and the incorporation of isotope into the urinary uric acid, urea, ammonia and creatinine was determined, in most instances in four hourly urine collections on day 1, thereafter in twenty-four hour urine samples to day 7. The measurements included not only the total uric acid-N 15 enrichment but also the N 15 abundance of each of the four uric acid nitrogens. Two noteworthy abnormalities were found in the patients with primary gout. One was in the initial intramolecular distribution of uric acid-N 15 , characterized by consistently disproportionate isotope enrichment of N-9 and N-3, both derived from the amide nitrogen of glutamine. The other was in the urinary total N 16 partition, characterized by a deficiency in urinary ammonium-N 15 excretion due to a defect in renal production of ammonia from glutamine. An abnormality of glutamine metabolism in primary gout is implied. It is suggested that the abnormality in glutamine metabolism described may have significance for the pathogenesis of primary gout. A defect in utilization of glutamine for renal production of ammonia (? glutaminase deficiency) might enhance uric acid production by recycling extra glutamine into the first and apparently rate-determining reaction of de novo purine biosynthesis, and moreover would predispose to uric acid stone formation.

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.

Effects of adrenocorticotropic hormone (ACTH) in gout

Abstract 1.1. ACTH effected a very rapid and satisfactory response in the local and systemic manifestations of acute gout in seven of eleven cases treated, including one patient refractory to colchicine. ACTH therefore appears to be a useful agent in the therapy of acute gout. In many of these patients, however, ACTH was not convincingly superior to colchicine, and in four instances colchicine terminated attacks responding unsatisfactorily to ACTH. Unlike colchicine, ACTH is not suitable for prophylactic use in the prevention of acute gouty attacks. 2.2. Exacerbation of symptoms occurred in four patients following discontinuance of ACTH therapy after a satisfactory response. Such exacerbations usually suggested re-exhibition of the underlying disease upon termination of the suppressive effects of ACTH rather than initiation of a new attack of acute gout. The conjoint and continued prophylactic use of colchicine seems rational in patients subject to frequent recurrences. 3.3. Acute gouty arthritis developed only once in eight cases of interval gout when ACTH was given in full dosage and then abruptly discontinued. 4.4. In the prevention and treatment of chronic tophaceous gout, the use of ACTH is neither feasible nor desirable at present. Salicylates and carinamide are at least as effective uricosuric agents, are readily available and orally administered. 5.5. The available evidence does not appear to justify the view that the pituitary and/or adrenal glands play a central role in the pathogenesis of gout.

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.

Current principles of management in gout

Abstract 1.1. Present knowledge concerning the fundamental nature of the gouty trait, the causes of acute gouty arthritis and the pathogenesis of chronic tophaceous gout, is reviewed. 2.2. The regulation of gout involves two more or less distinct problems: (1) prevention and suppression of attacks of acute gouty arthritis, which are not attributable to urate per se but to unknown causes; (2) prevention and mobilization of tophi, which represent excessive urate deposition in the tissues. Each problem requires specifically oriented management. Current principles of such management are outlined. 3.3. The three uses of colchicine, to terminate established attacks of acute gouty arthritis, to abort impending attacks, and as a prophylactic agent to prevent seizures in intercritical periods, are described and the results of each usage analyzed. The advantages of regular colchicine prophylaxis are stressed. 4.4. The use of corticotropin (ACTH) in acute gouty arthritis is described and the results in forty cases are presented. ACTH is usually effective if given in adequate dosage properly scheduled. 5.5. The use of phenylbutazone (butazolidine) in acute gouty arthritis is described and the results in twenty cases are presented. Administration is simple and relief is rapid and effective in most cases. Toxicity is low in short-term therapy. 6.6. The use of probenecid (benemid) as a uricosuric agent in chronic tophaceous gout is described. Experience with forty gouty subjects given daily dosage for six months to two years indicates that formation of new tophi and enlargement of old tophi can be prevented. Urate deposits in the tissues can be mobilized, with relief of chronic joint disability and shrinkage of visible tophi. 7.7. The conjoint use of restrictive diets to avoid precipitation of acute attacks and to minimize deposition of urate in the tissues is discussed.