Origins of the Uricosuric Response

Steele, Thomas H.; Boner, G

doi:10.1172/jci107309

Cited by 70 publications

(40 citation statements)

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“…However the possibility existed that pyrazinamide (or pyrazinoate generated) could have interfered with the renal actions of probenecid and chlorothiazide on a pharmacologic level. In the case of chlorothiazide some circumstantial evidence against this possibility was derived from observations that the natriurectic and phosphaturic responses to chlorothiazide were not affected by pyrazinamide pretreatment (9). Analogous evidence related to probenecid was more difficult to come by because this agent has little effect on cation or inorganic phosphate reabsorption.…”

Section: Comments On the Use Of Pyrazinamide Thomas H Steelementioning

confidence: 99%

Comments on the use of pyrazinamide

Steele

1975

Arthritis & Rheumatism

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In science there is a tendency to attempt simple explanations of complex phenomena. Renal physiology is no exception. For example, in measuring the net renal tubular secretion of a substance such as paminohippurate (PAH) as a function of either plasma PAH or the total PAH load to the kidney, an unknown amount of carrier-mediated PAH reabsorp tion occurs concomitantly (1). Yet such bidirectional transport often is conveniently ignored when transport occurs largely in one direction. In the case of uric acid in man, however, the recognition of its bidirectional transport is necessary for an adequate evaluation of renal urate handling. Although more urate is reabsorbed than is secreted, the existence of urate secretion appears mandatory if urate is to be eliminated at rates sufficient to establish homeostasis and to avoid hyperuricemia (2).Pyrazinamide has been utilized extensively to delineate the importance of each unidirectional component of urate transport. T h e "pyrazinamide suppression test," which measures the maximum decrement in urate excretion following pyrazinamide, was originated in this author's institution (3) and adopted by several others. T h e assumption underlying the test is that the antiuricosuric effect following pyrazinamide occurs secondary to inhibition of the tubular secretion of urate. Subsequent pharmacologic studies in man and animals by Weiner and Tinker (4) have upheld this assumption. T h e ultimate effects of pyrazinamide on renal transport systems are mediated by a metabolite, pyrazinoic acid. This compound appears to inhibit urate transport bidirectionally. Like many agents that affect urate transport, pyrazinoic acid mainly inhibits urate secretion at low plasma levels, but becomes significantly uricosuric at very high plasma concentrations (4,5). This "paradoxical effect" of pyrazinoate virtually rules out any possibility that the antiuricosuric state following pyrazinamide may derive from accelerated urate reabsorption. Furthermore the administration of pyrazinamide probably results in quite selective secretory inhibition. Limited observations in man indicate that only very low plasma pyrazinoate concentrations result from the oral administration of a large dose of pyrazinamide (4). Thus, following pyrazinamide administration. the low levels of metabolite ensure a predominantly antisecretory action, probably with only very minimal inhibition of urate reabsorption. Furthermore this antisecretory effect following pyrafor many hours (6); this stability allows the use of

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Section: Comments On the Use Of Pyrazinamide Thomas H Steelementioning

confidence: 99%

Comments on the use of pyrazinamide

Steele

1975

Arthritis & Rheumatism

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“…Thus rat there appears to be even less relationship between tlie urate clearance and urine flow than in man, a result that indirectly supports earlier rat microinjection studies indicating virtual impermeability of terminal nepliron segments to uric acid (36). Much of the evidence for a component of postsecretory reabsorption of urate in man has rested upon the finding that the uricosuric responses to various types of pharmacologic and chemical agents were either obliterated or greatly diminished by treatment with an antisecretory substance such as pyrazinamide (22) or low doses of salicylate (23). Because studies of that type left open the possibility that pyrazinoic acid or salicylate could have interfered with tlie action of the uricosuric compound on the basis of a pharmacologic interaction, the uricosuric response to 3y0 NaCl infusion, both with and without pyrazinamide treatment, was examined in 10 normal persons (25).…”

Section: Thomas H Steelementioning

confidence: 56%

“…Indirect inferential evidence for the reabsorption of some secreted urate in man has been gained by examining the renal responses to pyrazinamide in various disease states (20,21) and by following certain pharmacologic maneuvers (22) that result in an increased urate clearance. Low dosages of salicylate have been utilized, similarly to pyrazinamide, in order to inhibit urate secretion (23).…”

Section: Thomas H Steelementioning

confidence: 99%

“…Other reported examples of pyrazinamide-suppressible uricosuric responses include those following tlie administration of probenecid and intravenous clilorotliiazide (22), benziodarone (37), ethacrynic acid (33), certain radiographic contrast agents (38), and glycine (39). I n addition other studies have indicated that the liyperuricosuric states sometimes accompanying Wilson's disease (21) and Hodgkin's disease (20) may be largely pyrazinamide-suppressible.…”

Section: Thomas H Steelementioning

confidence: 99%

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Renal excretion of uric acid

Steele

1975

Arthritis & Rheumatism

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I n earlier years of renal physiology study, the developnient of the inulin clearance for the estimation of the glomerular filtration rate (GFR) allowed a precise comparison between the excretion and filtration rates of many urinary solutes. Although it soon was realized that many members of a large group of weak organic acids are avidly bound by the kidney and undergo net tubular secretion, studies in several species including man indicated that the rate of uric acid excretion was far less than its rate of filtration. Even though the possibility was raised that polymerized or protein-bound aggregates of urate not amenable to glomerular filtration might exist in plasma (l), the prevailing opinion was that urate simply underwent complete glomerular filtration and partial tubular reabsorption. Extensive studies were reported in 1950 by Berliner et al (Z), in which urate titration procedures were performed in an attempt further to characterize urate reabsorption within the normal kidney. During the progressive infusion of urate, the difference between the rates of filtration and excretion of urate increased progressively. Berliner and his coworkers ultimately concluded that a maximum urate reabsorption rate probably exists in normal man, but that the ap- parent capacity for urate reabsorption is so great that it would not become fully saturated under normal conditions (2). Although Praetorius and Kirk (3) described a hypouricemic patient who demonstrated net urate secretion in 1950, the possible existence of a significant amount of tubular secretion of urate in man was not widely accepted. Subsequently, renewed interest in renal urate secretion occurred, largely as a result of work from the laboratory of the late Dr. Alexander Gutman. Gutman and Y u raised the question of the existence of urate secretion in man based on observations during clearance studies in gouty patients and normal persons (4). Even in their early reports, they hypothesized that large transtubular fluxes of urate might exist, for if secretion of urate did occur then the calculated net reabsorptive rates of urate would be too low. Subsequent observations elucidating the remarkable "paradoxical actions" of certain pharmacologic agents on urate excretion (5) and also the antiuricosuric effect of pyrazinamide (PZA) administration (6) raised the possibility that inhibition of the tubular secretion of urate could substantially reduce urate excretion. Although Gutman and his colleagues acknowledged that an enhanced rate of urate reabsorption could also have produced an antiuricosuric effect, they visualized that if virtually complete reabsorption of the filtered urate occurred within the nephron and if the urinary uric acid were derived primarily from

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“…Until recently the clinical application of the "pyrazinamide suppression test" has not been challenged; however the analysis of several new studies has suggested that the premises underlying this test are not valid (4). Subsequently, Steele and Boner (5) and Diamond and Paolino (6) initiated studies that have examined the effect of PZA when administered in combination with other agents that alter uric acid excretion and they have proposed a new model by which the human kidney transports uric acid. This model differs from the earlier one in that uric acid is reabsorbed at a site distal to the point of uric acid secretion.…”

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confidence: 99%