Nephron 14: 21-32 (1975)
Renal Urate Excretion in Normal Man T homas H. Steele and R ichard E. R ieselbach Department of Medicine, The University of Wisconsin Center for Health Sciences, Madison, Wise.
In earlier years of this century, evolving concepts of normal renal physio logy were intimately involved with postulates regarding the tubular handling of certain organic acids [14]. Indeed, observations in several species regarding the capacity of renal tubules to secrete phenol red, and related compounds, led to a revival of interest in the modifications in the composition of tubular fluid which could occur through means other than solute and water reabsorp tion [14]. Not surprisingly, uric acid also was investigated in several species because of its position as an end product of purine metabolism in man and certain great apes, as well as its being the nitrogenous end product of protein catabolism in avian species. Indeed, by demonstrating the presence of exceed ingly large amounts of uric acid in the urine of the chicken, M ayrs [26] virtually demonstrated the net secretion of urate by the chicken kidney, as early as 1924. With continued growth of knowledge regarding normal renal physiology, and particularly with the development of the inulin clearance as an accurate estimation of the glomerular filtration rate, precise comparisons of the ex cretion rates of many substances with their concomitant rates of filtration
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
Abstract. The development of our knowledge of the intrarenal Key Words processes involved in the control of urate excretion in normal man is Uric acid summarized. Although there are many gaps in our current knowledge, Urate and different interpretations may be given to the available data, cur- Organic acids rent evidence seems to favor the existence of extensive tubular reab- Tubular secretion sorption of urate following its glomerular filtration. Subsequently, tubular secretion of urate and the reabsorption of an unknown amount of the secreted urate probably take place. For reasons discussed, it seems most likely that the regulation and control of urate excretion are accomplished through modulations in tubular secretion, postsecretory reabsorption, or both.
22
S teele /R ieselbach
could be made. In man and several animal species, it soon became apparent that the renal excretion of uric acid was far less than its simultaneous rate of filtration, thereby implying extensive tubular reabsorption of the compound. Although the possibility was suggested that aggregates of urate in plasma could produce polymerized (and possibly protein-bound) species which would not undergo glomerular ultrafiltration [3], the most widely held hypothesis was that renal urate excretion was determined solely by glomerular filtration and subsequent tubular reabsorption. In 1950, B erliner et al.[4] infused lithium urate into volunteers in an attempt to investigate the mechanism of urate handling by the normal kidney. In their studies, marked elevations in the filtered load of urate were obtained because of hyperuricemia, and the difference between filtered and excreted urate increased progressively. The authors concluded that the maximum rate of urate reabsorption in normal man must be of the order of 15 mg/min, but they also stipulated that the capacity for urate reabsorption must be so great that it almost certainly remains unsaturated in the normal course of events. In the same year, P raetorius and K irk [29] described a patient with marked hypouricemia, a ‘fractional urate clearance’ of 1.46, and elevated oxypurine levels. They concluded that urate must be secreted or synthesized by the kidney. However, because of the great disparity between urate handling in their patient and that occurring in normal man, their hypothesis of urate secretion was not widely applied to normal man.
In 1957, G utman and Yu [17] raised the question of tubular secretion of urate in man. Underlying their speculations were results of investigations conducted in a large number of gouty patients to examine the possibility that abnormal renal urate handling might contribute to the pathogenesis of gouty hyperuricemia. They suggested that, if tubular secretion of urate did occur, then calculated ‘net’ rates of urate reabsorption would be too low. Subsequently, data regarding the paradoxical retention of uric acid following a low dosage of uricosuric drugs [43] and also the marked antiuricosuric effect of pyrazinamide administration [40,42] suggested that pharmacologic inhibition of tubular secretion could have explained both types of conditions. Although it was acknowledged that a pharmacologically induced enhance ment of urate reabsorption could have produced these antiuricosuric effects equally well, G utman et al. postulated that virtually complete reabsorption
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
Resurgence o f Interest in Urate Secretion
Urate Handling in Normals
23
of the filtered urate might occur as filtrate traversed the nephron, and that the uric acid ultimately appearing in the urine could be derived primarily from tubular secretory mechanisms [17]. Subsequent studies in the dog [41] and man [19] placed this possibility in the realm of scientific observation. In the case of man, net secretion of uric acid by as much as 20% of the amount filtered could be demonstrated in persons with mild renal insufficiency after the administration of a potent uricosuric agent and an osmotic diuretic, during the infusion of uric acid [19]. Since net secretion of urate had been demonstrated when urate reabsorption probably was only incompletely inhibited, it seemed logical that the true magnitude of intrarenal urate secretion could have been greater than the 20% figure suggested by the urate-to-inulin clearance ratio. In 1959 [19] and sub sequently in 1964 [16], G utman suggested in addition that large quantities of urate might be secreted by the tubules, with a portion of the secreted urate ulti mately undergoing tubular reabsorption prior to the release of any urate into the urine. Thus, in those relatively early studies, the possibility of urate reab sorption, either distal to or coextensive with secretion, was suggested.
In 1961, the ‘three-component hypothesis’ for renal urate handling was proposed by G utman and Yu [18]. According to that formulation, urate is almost entirely filterable by glomeruli, is reabsorbed for the most part by an active tubular transport process, and also is secreted by other transport mech anisms [18]. Although the authors suggested that all three components par ticipate in the normal regulation of urate excretion by the mammalian kidney, the relative contributions of the reabsorptive and secretory components were uncertain. Only the filtered load could be measured with confidence. The same workers also were the first to provide some quantitative indication of the importance of tubular secretion. When the plasma urate was markedly increased in man by urate loading, and pyrazinoic acid administered, urate excretion declined markedly [39]. Assuming that pyrazinoic acid served mainly to inhibit the tubular secretion of urate, the continuing antiuricosuric response to this pharmacologic agent during urate loading indirectly suggested that the tubular secretion of urate normally increases as the plasma urate is increased by exogenous loading. Although the antiuricosuric properties of pyrazinamide and pyrazinoic acid had been described [39,40,42], detailed knowledge of the metabolism
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
Pharmacological Characterization of Urate Transport
Steele/ R ieselbach
and the pharmacology of these compounds was lacking. Nevertheless, it had been assumed that pyrazinamide administration resulted in a rather selective inhibitory effect on the tubular secretion of urate, possibly occurring second ary to the direct renal action of a metabolite of pyrazinamide [40], Although the action of pyrazinamide on urate handling differed in some species, stopflow studies in the dog indicated the selective inhibition of a ‘secretory peak’ for 14C-labeled uric acid [7]. In contrast, it seemed unlikely (although still remotely possible) that pyrazinamide could result in the enhancement of an active tubular reabsorptive process. Given this background, an attempt was made to roughly estimate urate secretion and reabsorption in normal persons by measuring the maximal decre ment in urate excretion produced by pyrazinamide [36], In order to interpret the results, it was assumed that pyrazinamide results in the virtually complete and selective inhibition of tubular secretion of urate, and also that intrarenal urate secretion and reabsorption do not influence or interfere with one another. Accordingly, the decrement in urate excretion produced by pyrazinamide was interpreted as a minimum estimate of the tubular secretion of urate, while the urinary urate remaining during the action of pyrazinamide was taken to represent the maximum amount of filtered urate that could have escaped tubular reabsorption [36]. This estimate of tubular secretion of urate, the decrement in urate excretion produced by pyrazinamide, varied in a rather direct manner with the plasma urate concentration. In the ten normal persons studied, the plasma urate levels were both raised and lowered through pharma cologic manipulations. The pyrazinamide-induced decrement in excretion always varied directionally with changes in the plasma urate. In addition, over the entire range of plasma urate levels studied, urate reabsorption after pyrazinamide treatment was virtually complete. Those observations suggested that the human kidney normally responds to increased availability of urate, both at the secretory and reabsorptive transport sites, by increasing the rates of bidirectional transport. An increase in the apparent secretory rate appeared to be the primary mechanism whereby urate excretion could increase during hyperuricemia. Accordingly, the results suggested that renal urate homeostasis resides primarily within the secretory system. Similar results subsequently were obtained by G utman et al. [20], As already mentioned, one assumption underlying the interpretation of the ‘pyrazinamide suppression test’ was that pyrazinamide administration causes the selective and effective inhibition of tubular secretion of urate. In contrast, data obtained by F anelli et al. [12] in the Cebus monkey were inter preted as indicating that pyrazinoic acid accelerates the reabsorption of urate.
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
24
25
Subsequent pharmacologic studies in other species, however, have indicated that the antiuricosuric effect elicited by pyrazinamide administration can be attributed to a direct renal action of a metabolite, pyrazinoic acid [37]. In the dog and Cebus monkey, pyrazinoic acid is secreted by renal tubules, probably by the mechanism also secreting hippurates and other organic anions [37]. Furthermore, studies with pyrazinoic acid in the dog [37] and chimpanzee [13] indicated that this compound exerts a dual and ‘paradoxical’ action on renal urate handling. In a manner reminiscent of salicylates and certain other organic anions [43], pyrazinoate at plasma concentrations less than 100 fxg/ml caused a striking antiuricosuric response similar to that which occurs after pyrazinamide administration. At high plasma concentrations, however, pyr azinoate was markedly uricosuric in both species [13,37], This inhibition of urate reabsorption by pyrazinoic acid makes the possibility of accelerated urate reabsorption by pyrazinoate unlikely, in that simultaneous acceleration and inhibition of the same transport mechanism by the same chemical agent would be required. After the administration of the dose of pyrazinamide utilized in the ‘pyrazinamide suppression test’, probably only a small amount of the pyra zinoic acid metabolite is formed; this would serve to inhibit tubular urate secretion rather selectively [37], Nevertheless, a certain small inhibitory action of pyrazinoate on reabsorption cannot be excluded, even at low plasma pyrazinoate levels. In addition, the degree of secretory inhibition occurring during the maximum antiuricosuric action could be incomplete. Thus, the test provides a minimal estimate of urate secretion. Subsequently, certain confusing observations regarding urate handling in disease were reported when the pyrazinamide test was utilized more widely. Hypouricemic patients with Wilson’s disease [38] and Hodgkin’s disease [2], who had elevated urate clearance values, underwent ‘pyrazinamide suppres sion tests’ in attempts to document the site of their inappropriate renal urate loss. To the surprise of most observers, the results suggested inappropriately elevated urate secretion values and normal reabsorption. Whereas renal clear ance values initially were elevated, the urine became virtually urate-free after pyrazinamide administration. The obvious interpretation that disease-induced excessive renal urate losses might stem from inappropriately elevated tubular secretion of urate ran counter to the long accepted notion that such hypou ricemic states probably result from a diminished rate of (proximal) tubular reabsorption of filtered urate as a result of disease-induced tubular lesions. In addition, certain surprising pharmacological observations were re ported. According to the classical formulation in which urate first is filtered,
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
Urate Handling in Normals
S teele/ R ieselbach
then is reabsorbed, and subsequently secreted, the inhibition of tubular sec retion should not affect incremental responses to uricosuric agents. To give an example, the administration of probenecid to a person excreting uric acid at a rate of 400 ¡xg/min could result in a urate excretion rate of 1,400 ¡xg/min, or an incremental response of 1,000 ¡xg/min. After pretreatment with pyrazinamide, baseline urate excretion might be on the order of 50 ¡xg/min, but one would expect the same probenecid-induced incremental uricosuric response of 1,000 ¡xg/min, giving a total urate excretion rate of 1,050 ¡xg/min after both pyrazinamide and probenecid. In contrast, both in the chimpanzee [9] and man [8,35], incremental uricosuric responses to probenecid were virtually abolished by pretreatment with pyrazinamide or pyrazinoate. In addition, the uricosuric responses to intravenous chlorothiazide [35] or aggressive volume expansion with hypertonic sodium chloride [25] were diminished substantially by pretreatment with pyrazinamide. Although the data could have been interpreted as indicating that probenecid, chlorothiazide, and hypertonic sodium chloride infusions all elicited uricosuric responses through a stimulation of the tubular secretion of urate, this interpretation seemed unlikely and even untenable. In contrast to the traditional and rather tacit assumption that urate reab sorption precedes secretion in entirety, recent experiments employing two animal models have indicated that at least some tubular reabsorption of urate may occur coextensively with or following urate secretion in the nephron. In the first micropuncture study of urate handling by the rat kidney in which tubular fluid urate was determined by a microchemical method, the ‘fraction of filtered urate remaining’ at the late proximal tubule substantially exceeded the amount filtered, indicating net secretion of urate by proximal tubules of superficial nephrons in the rat kidney [15]. Yet, simultaneous whole-kidney urate clearances were far less than the glomerular filtration rate [15]. Assuming that the values obtained in superficial nephrons reflected the kidney as a whole, substantial reabsorption of urate must have occurred following its secretion. In subsequent studies in the rat, the net accumulation of urate in proximal tubular fluid appeared to result from a rapid secretory influx of urate across proximal tubular epithelium which was not counterbalanced by equally rapid efflux [23,24]. However, an animal model utilizing a species more closely resembling man would have been more satisfying. In recent years, the chimpanzee has proved to be such an animal model, with physiologic and pharmacologic reactivity analogous to man insofar as renal urate handling is concerned [9,10]. In the chimpanzee, under control clearance conditions, urate excretion normally is far less than the amount
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
26
27
filtered. Yet, after administration of mersalyl, net secretion of urate was clearly demonstrable [11], Indeed, the magnitude of secretion was surprising; urate clearances achieved values nearly double the glomerular filtration rate on occasion [11], The fact that the inhibition of urate reabsorption by mersalyl in the chimpanzee led to the demonstration of such high values of net urate secretion, indicated that the magnitude of intrarenal urate secretion normally must be far greater than the amount excreted. The ‘unmasking’ of extensive urate secretion in the chimpanzee occurred through the inhibition of urate reabsorption by mersalyl, implying that a substantial amount of secreted urate normally is reabsorbed in that species. This reabsorption of secreted urate could occurcoextensively with secretion, as suggested by the bidirectional urate tracer flux studies in the rat proximal tubule [23], or alternatively could occur discretely at sites distal to those where tubular secretion of urate takes place. The discrimination between these two possibilities has not yet been ac complished. The concept of postsecretory urate reabsorption can be utilized to explain suppression of the uricosuric responses to various pharmacologic agents upon inhibition of tubular secretion of urate with pyrazinamide. If the tubular secretion of urate is great in magnitude, then postsecretory reabsorption also must be of a similar or greater order of magnitude, since the amount of urate excreted in man normally is less than 12% of the amount filtered. If post secretory reabsorption were inhibited by a pharmacologic agent or partially impaired by a disease process, it is easy to visualize how the inhibition of tubular secretion of urate (with pyrazinamide) could ablate the uricosuric state. By inhibiting tubular secretion, less urate would be delivered to post secretory reabsorptive sites. Under those conditions, urate might be almost completely extracted from tubular fluid, despite pharmacologic transport inhibition or damage to transport mechanisms by disease. Alternatively, if it is assumed that extensive urate reabsorption occurs prior to any secretion in the nephron, then the inhibition of presecretory reabsorption by drugs or disease would increase the amount of urate delivered distally. Both filtered urate escaping reabsorption and urate derived from tubular secretion would be delivered to postsecretory sites. Depending on the transport characteristics of the postsecretory site, inhibition of urate secretion by pyrazinamide might decrease the load sufficiently to enable virtually complete reabsorption. Thus, it is conceivable that a pharmacologic agent eliciting a uricosuric response which is suppressible by pyrazinamide might act to inhibit urate reabsorption either at presecretory or postsecretory reabsorptive sites, or both. The above formulations depend upon the existence of presecretory reab
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
Urate Handling in Normals
28
S teele/R ieselbach
sorption in a substantial amount. Based on work in the chimpanzee it has been suggested that the presecretory reabsorption may not occur at all [13] but that tubular secretion may be the initial transport event, accompanied or followed by coextensive or postsecretory reabsorption. On teleological grounds alone, this formulation is unattractive because it permits the accumu lation of large amounts of urate in tubular fluid, thereby accentuating the danger of intraluminal uric acid precipitation. This situation could have especially serious consequences in man and other species devoid of uricase, in whom uric acid is the end product of purine degradative metabolism. Recent experiments in man have addressed the particular question of the existence of presecretory reabsorption. In those studies, normal persons were simultaneously treated with pyrazinamide and yeast RNA over a period of several days in order to significantly elevate their plasma urate concentrations, and then underwent renal clearance studies at hyperuricemic plasma urate levels [21]. Irrespective of the level of the plasma urate concentration, the fractional reabsorption of urate after pyrazinamide pretreatment always exceeded 98% of the filtered load [21]. Those data indicate that, in the absence of tubular secretion (inhibited by pyrazinamide), urate reabsorption is ex tremely extensive. In contrast, when urate secretion presumably is intact, it is well known that urinary uric excretion increases greatly during the hyper uricemia accompanying RNA loading [36]. Thus, it seems likely that com bined magnitude of presecretory plus postsecretory reabsorption is far greater that that of postsecretory reabsorption alone.
Unanswered Questions and Possible Directions for Future Research
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
In this review, we have attempted to summarize the many stages through which our present concepts of renal urate handling in man (and several other animal species) have evolved. Indeed, it is apparent that many questions remain unresolved. For example, the existence of postsecretory reabsorption in man could explain many of the rather surprising results obtained utilizing the ‘pyrazinamide suppression test’ in certain disease entities. Nevertheless, direct evidence for postsecretory reabsorption has been obtained only in animal models. To date, no animal model studied exhibits all the character istics of renal urate handling in man. Preferably, any animal model should resemble man as closely as possible. Clearly the rabbit seems to reflect the human condition poorly, for that ‘hypouricemic’ species contains uricase and, in addition, excretes large
Urate Handling in Normals
29
amounts of urate relative to the amount filtered [27], The Dalmatian, an animal with a renal reabsorptive defect for uric acid, also contains uricase in an apparently inaccessible form - possibly reflecting a hepatic transport defect analogous to its renal reabsorptive defect [44], The rat, an animal long favored for laboratory experimentation for economic and other reasons, has been used extensively in recent studies of urate handling [1,6,15,22-24], Although the rat demonstrates substantial intrarenal urate secretion, as well as extensive postsecretory urate reabsorption, it is presently unclear to what extent the intrarenal synthesis of urate contributes to these phenomena [30], Likewise, the mongrel dog has some of the same disadvantages, in that it is a species with both intrarenal urate synthesis [31] and uricase. The Cebus monkey has been ammenable to both classical clearance [12,34] and micropuncture [32] methodologies for the exploration of its renal urate handling. The Cebus monkey has considerable attributes for this type of study, in that its uricosuric responses to many pharmacologic agents are similar to those obtained in man [34], On the other hand, S im k in [33] has shown that the Cebus monkey is a marked overproducer of uric acid, and that its relatively normal plasma urate concentrations (in the presence of uricase) reflect an increased uric acid production and turnover rate. Moreover, the Cebus monkey, like the mongrel dog and rabbit, displays certain dissimilarities to man with respect to organic anion handling. While it appears that hippurates and urate can compete for common secretory transport pathways in the Cebus monkey [12], the mongrel dog [28], rabbit [27], and rat [6,22], recent studies have indicated that this is unlikely in man [5] and the chimpanzee [9], where p-aminohippurate and urate secretion probably occur independently of one another. Finally, the chimpanzee might be the ideal representation of man in a lower species. Indeed, W einer and F anelli have published data in this symposium, from studies employing allopurinol infusion, which indicate that intrarenal urate synthesis cannot be an important factor regulating the minute-to-minute urate excretion in the chimpanzee. Unfortunately, the chimpanzee exhibits one very notable difference in urate handling when compared to man. Although mersalyl administration in the chimpanzee results in the net se cretion of uric acid [11], this may reflect a tendency of that species toward hyperresponsiveness to uricosuric agents [10]. The administration of the same dose of this mercurial to man elicits a more modest uricosuric response which falls far short of demonstrating net secretion1 [F a n elli ]. Thus, to date, no animal model studied totally reflects renal urate handling in man.
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
1 Added in proof: F anelli, G .M .; H itzenberger, G .: Uricosuric activity of intravenous mersalyl in man. Medikon Internat. 30-4: 2 (1974).
30
S teele /R ieselbach
It should be apparent from the above considerations, that our under standing of urate transport in man is incomplete. Currently, it appears that man is the ideal species for the study of at least some aspects of urate transport because results from other species may not be applicable. For example, the detailed study of certain defects in urate reabsorption in man could very likely enhance our knowledge of normal renal urate handling. On the other hand, in order to genuinely advance knowledge through study in man, new ap proaches in methodology presently are needed. Whether such approaches will be pharmacological or more direct remains to be seen. However, it is likely that appropriate investigational techniques ultimately will answer many of the remaining questions in this field. These answers should be relevant to the many unresolved problems related to abnormal urate homeostasis. Some of these clinical problems will be considered in detail in subsequent contributions to this symposium. References
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
1 A bramson, R. G. ; K atz, J. H. ; M aesaka, J. K., and Levitt, M. F. : Uric acid transport in rat kidney. Proc. amer. Soc. clin. Invest, la (1973). 2 Bennet, J.S.; Bond , J.; Singer , I., and G ottlieb, A.V.: Hypouricemia in Hodgkin’s disease. Ann. intern. Med. 76: 751-756 (1972). 3 Berglund , H. and F risk, A. R. : Uric acid elimination in man. Acta med. scand. 86: 128-135(1935). 4 Berliner, R. W. ; H ilton, J. G. ; Yil, T.-F., and K ennedy, T. J., jr. : The renal mechanism for urate excretion in man. J. clin. Invest. 29: 396-401 (1950). 5 Boner, G. and Steele, T. H. : Relationship of urate and p-aminohippurate secretion in man. Amer. J. Physiol. 225: 100-104 (1973). 6 Boudry, J. F. : Effet d’inhibiteurs des transports transtubulaires sur l’excrétion rénale d’acide urique chez le rat. Pflügers Arch. ges. Physiol. 328: 279-291 (1971). 7 D avis, B.B.; F ield , J.B.; R odnan, G .P., and K edes, L.H .: Localization and pyrazinamide inhibition of distal trans-tubular movement of uric acid-2-14C with a modified stop-flow technique. J. clin. Invest. 44: 716-721 (1965). 8 D iamond, H. S. and P aolino, J. S. : Evidence for a post-secretory rcabsorptive site for uric acid in man. J. clin. Invest. 52: 1491-1499 (1973). 9 F anelu , G. M.,jr. ; Bohn , D., and R eilly, S.S. : Renal urate transport in the chimpanzee. Amer. J. Physiol. 220: 613-620 (1971). 10 F anelu , G. M., jr. ; Bohn, D. L., and R eilly, S. S. : Renal effects of uricosuric agents in the chimpanzee. J. Pharmacol, exp. Ther. 177: 591-599 (1971). 11 F anelu , G .M .; Bohn, D .L .; R eilly, S.S., and W einer, I.M .: Effects of mercurial diuretics on renal transport of urate in the chimpanzee. Amer. J. Physiol. 224:985-992 (1973). 12 F anelli, G. M., jr. ; Bohn , D.L., and Stafford, S. : Functional characteristics of renal urate transport in the Cebus monkey. Amer. J. Physiol. 218: 627-636 (1970).
31
13 F anelli, G.M ., jr. and W einer, I.M .: Pyrazinoate excretion in the chimpanzee. Relation to urate disposition and the actions of uricosuric drugs. J. clin. Invest. 52: 1946-1957(1973). 14 F orster, R .P .: Renal transport mechanisms. Fed. Proc. 26: 1008-1019 (1967). 15 G reger, R.; L ang , F., and D eetjen, P .: Handling of uric acid by the rat kidney. I. Microanalysis of uric acid in proximal tubular fluid. Pflügers Arch. ges. Physiol. 324: 279-287(1971). 16 G utman, A. B.: Significance of the renal clearance of uric acid in normal and gouty man. Amer. J. Med. 37: 833-838 (1964). 17 G utman, A. B. and Y ü, T .-F. : 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. Amer. J. Med. 23: 600-622 (1957). 18 G utman, A.B. and YÜ, T.-F.: A three-component system for regulation of renal ex cretion of uric acid in man. Trans. Ass. amer. Physicians 74: 353-365 (1961). 19 G utman, A.B.; YÜ, T.-F., and Berger, L.: Tubular secretion of urate in man. J. clin. Invest. 38: 1778-1781 (1959). 20 G utman, A.B.; YÜ, T.-F., and Berger, L.: Renal function in gout. HI. Estimation of tubular secretion and reabsorption of uric acid by use of pyrazinamide (pyrazinoic acid). Amer. J. Med. 47: 575-592 (1969). 21 J enkins, P. and R ieselbach, R .E .: Unique characteristics of the mechanism for reab sorption of filtered versus secreted urate. Proc. amer. Soc. clin. Invest. 36a: (1974). 22 K ramp, R.W .; Lassiter, W.E., and G ottschalk, C.W.: Urate-2-14C transport in the rat nephron. J. clin. Invest. 50: 35-48 (1971). 23 L ang, F .; G reger, R., and D eetjen, P .: Handling of uric acid by the rat kidney. II. Microperfusion studies on bidirectional transport of uric acid in the proximal tubule. Pflügers Arch. ges. Physiol. 335: 257-265 (1972). 24 Lang , F.; G reger, R., and D eetjen, P.: Handling of uric acid by the rat kidney. III. Microperfusion studies on steady state concentration of uric acid in proximal tubule. Consideration of free flow conditions. Pflügers Arch. ges. Physiol. 338: 295-302 (1973). 25 M anuel, M. A. and Steele, T. H .: Pyrazinamide suppression of the uricosuric response to sodium chloride infusion. J. Lab. clin. Med. 83:417-427 (1974). 26 M ayrs, E. G .: Secretion as a factor in elimination by the bird’s kidney. J. Physiol., Lond. 58: 276-284 (1924). 27 M öller, J.V.: The relation between secretion of urate and p-aminohippurate in the rabbit kidney. J. Physiol., Lond. 192: 505-517 (1967). 28 N olan, R.P. and Foulkes, E. C .: Studies on renal urate secretion in the dog. J. Pharma col. exp. Ther. 179: 429-437 (1971). 29 Praetorius, E. and K irk , J. E .: Hypouricemia: with evidence for tubular elimination of uric acid. J. Lab. clin. Med. 35: 856-868 (1950). 30 Q uebbemann, A .J.: Renal synthesis of uric acid. Amer. J. Physiol. 224: 1398-1402 (1973). 31 Q uebbemann, A. J. and C umming, D .: Renal synthesis of uric acid in isolated perfused dog kidneys. Abstr. amer. Soc. Nephrol. 6: 85 (1973). 32 R och -R amel, F. and W einer, I . M.: Excretion of urate by the kidneys in Ccbus monkeys. A micropuncture study. Amer. J. Physiol. 224: 1369-1974 (1973). 33 Simkin , P. A .: Uric acid metabolism in Cebus monkeys. Amer. J. Physiol. 221:1105-1109 (1971).
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
Urate Handling in Normals
32
S teele/R ieselbach
Request reprints from: T homas H. Steele, MD, 1300 University Avenue, Madison, W153706 (USA)
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
34 Skeith , M. D. and H ealey, L. A .: Urate clearance in Cebus monkeys. Amer. J. Physiol. 214: 582-584 (1968). 35 Steele, T. H. and Boner, G .: Origins of the uricosuric response. J. clin. Invest. 52: 1368-1375 (1973). 36 Steele, T. H. and R ieselbach, R. E .: The renal mechanism for urate homeostasis in normal man. Amer. J. Med. 43: 868-875 (1967). 37 W einer, I.M. and T inker , J.P.: Pharmacology of pyrazinamide: metabolic and renal function studies related to the mechanism of drug-induced urate retention. J. Pharmacol, exp. Ther. 180: 411-434 (1972). 38 W ilson, D. M. and G oldstein, N. P .: Renal urate excretion in patients with Wilson’s Disease. Kidney Int. 4: 331-336 (1973). 39 Yi), T.-F.; Berger, L., and G utman, A.B.: Renal function in gout. II. Effect of uric acid loading on renal excretion of uric acid. Amer. J. Med. 3 3 :829-844 (1962). 40 Y u, T .-F.; Berger, L., and G utman, A. B.: Suppression of tubular secretion of urate by pyrazinamide in the dog. Proc. Soc. exp. Biol. Med. 107: 905-908 (1961). 41 Yu, T.-F.; Berger, L.; K upfer , S., and G utman, A.B.: Tubular secretion of urate in the dog. Amer. J. Physiol. ¡99: 1199-1204 (1960). 42 Yu, T.-F.; Berger, L.; Stone, D .J.; W olf, J., and G utman, A.B.: Effect of pyrazin amide and pyrazinoic acid on urate clearance and other discrete renal functions. Proc. Soc. exp. Biol. Med. 96: 264-267 (1957). 43 Yu, T.-F. and G utman, A.B.; A study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanism for excretion of urate in man. J. clin. Invest. 38: 1298-1315 (1959). 44 Yu, T.-F.; G utman, A.B.; Berger, L., and K aung, C .: Low uricase activity in the dalmatian dog simulated in mongrels given oxonic acid. Amer. J. Physiol. 220:973-979 (1971).
Renal Urate Excretion in Normal Man T homas H. Steele and R ichard E. R ieselbach Department of Medicine, The University of Wisconsin Center for Health Sciences, Madison, Wise.
In earlier years of this century, evolving concepts of normal renal physio logy were intimately involved with postulates regarding the tubular handling of certain organic acids [14]. Indeed, observations in several species regarding the capacity of renal tubules to secrete phenol red, and related compounds, led to a revival of interest in the modifications in the composition of tubular fluid which could occur through means other than solute and water reabsorp tion [14]. Not surprisingly, uric acid also was investigated in several species because of its position as an end product of purine metabolism in man and certain great apes, as well as its being the nitrogenous end product of protein catabolism in avian species. Indeed, by demonstrating the presence of exceed ingly large amounts of uric acid in the urine of the chicken, M ayrs [26] virtually demonstrated the net secretion of urate by the chicken kidney, as early as 1924. With continued growth of knowledge regarding normal renal physiology, and particularly with the development of the inulin clearance as an accurate estimation of the glomerular filtration rate, precise comparisons of the ex cretion rates of many substances with their concomitant rates of filtration
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
Abstract. The development of our knowledge of the intrarenal Key Words processes involved in the control of urate excretion in normal man is Uric acid summarized. Although there are many gaps in our current knowledge, Urate and different interpretations may be given to the available data, cur- Organic acids rent evidence seems to favor the existence of extensive tubular reab- Tubular secretion sorption of urate following its glomerular filtration. Subsequently, tubular secretion of urate and the reabsorption of an unknown amount of the secreted urate probably take place. For reasons discussed, it seems most likely that the regulation and control of urate excretion are accomplished through modulations in tubular secretion, postsecretory reabsorption, or both.
22
S teele /R ieselbach
could be made. In man and several animal species, it soon became apparent that the renal excretion of uric acid was far less than its simultaneous rate of filtration, thereby implying extensive tubular reabsorption of the compound. Although the possibility was suggested that aggregates of urate in plasma could produce polymerized (and possibly protein-bound) species which would not undergo glomerular ultrafiltration [3], the most widely held hypothesis was that renal urate excretion was determined solely by glomerular filtration and subsequent tubular reabsorption. In 1950, B erliner et al.[4] infused lithium urate into volunteers in an attempt to investigate the mechanism of urate handling by the normal kidney. In their studies, marked elevations in the filtered load of urate were obtained because of hyperuricemia, and the difference between filtered and excreted urate increased progressively. The authors concluded that the maximum rate of urate reabsorption in normal man must be of the order of 15 mg/min, but they also stipulated that the capacity for urate reabsorption must be so great that it almost certainly remains unsaturated in the normal course of events. In the same year, P raetorius and K irk [29] described a patient with marked hypouricemia, a ‘fractional urate clearance’ of 1.46, and elevated oxypurine levels. They concluded that urate must be secreted or synthesized by the kidney. However, because of the great disparity between urate handling in their patient and that occurring in normal man, their hypothesis of urate secretion was not widely applied to normal man.
In 1957, G utman and Yu [17] raised the question of tubular secretion of urate in man. Underlying their speculations were results of investigations conducted in a large number of gouty patients to examine the possibility that abnormal renal urate handling might contribute to the pathogenesis of gouty hyperuricemia. They suggested that, if tubular secretion of urate did occur, then calculated ‘net’ rates of urate reabsorption would be too low. Subsequently, data regarding the paradoxical retention of uric acid following a low dosage of uricosuric drugs [43] and also the marked antiuricosuric effect of pyrazinamide administration [40,42] suggested that pharmacologic inhibition of tubular secretion could have explained both types of conditions. Although it was acknowledged that a pharmacologically induced enhance ment of urate reabsorption could have produced these antiuricosuric effects equally well, G utman et al. postulated that virtually complete reabsorption
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
Resurgence o f Interest in Urate Secretion
Urate Handling in Normals
23
of the filtered urate might occur as filtrate traversed the nephron, and that the uric acid ultimately appearing in the urine could be derived primarily from tubular secretory mechanisms [17]. Subsequent studies in the dog [41] and man [19] placed this possibility in the realm of scientific observation. In the case of man, net secretion of uric acid by as much as 20% of the amount filtered could be demonstrated in persons with mild renal insufficiency after the administration of a potent uricosuric agent and an osmotic diuretic, during the infusion of uric acid [19]. Since net secretion of urate had been demonstrated when urate reabsorption probably was only incompletely inhibited, it seemed logical that the true magnitude of intrarenal urate secretion could have been greater than the 20% figure suggested by the urate-to-inulin clearance ratio. In 1959 [19] and sub sequently in 1964 [16], G utman suggested in addition that large quantities of urate might be secreted by the tubules, with a portion of the secreted urate ulti mately undergoing tubular reabsorption prior to the release of any urate into the urine. Thus, in those relatively early studies, the possibility of urate reab sorption, either distal to or coextensive with secretion, was suggested.
In 1961, the ‘three-component hypothesis’ for renal urate handling was proposed by G utman and Yu [18]. According to that formulation, urate is almost entirely filterable by glomeruli, is reabsorbed for the most part by an active tubular transport process, and also is secreted by other transport mech anisms [18]. Although the authors suggested that all three components par ticipate in the normal regulation of urate excretion by the mammalian kidney, the relative contributions of the reabsorptive and secretory components were uncertain. Only the filtered load could be measured with confidence. The same workers also were the first to provide some quantitative indication of the importance of tubular secretion. When the plasma urate was markedly increased in man by urate loading, and pyrazinoic acid administered, urate excretion declined markedly [39]. Assuming that pyrazinoic acid served mainly to inhibit the tubular secretion of urate, the continuing antiuricosuric response to this pharmacologic agent during urate loading indirectly suggested that the tubular secretion of urate normally increases as the plasma urate is increased by exogenous loading. Although the antiuricosuric properties of pyrazinamide and pyrazinoic acid had been described [39,40,42], detailed knowledge of the metabolism
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
Pharmacological Characterization of Urate Transport
Steele/ R ieselbach
and the pharmacology of these compounds was lacking. Nevertheless, it had been assumed that pyrazinamide administration resulted in a rather selective inhibitory effect on the tubular secretion of urate, possibly occurring second ary to the direct renal action of a metabolite of pyrazinamide [40], Although the action of pyrazinamide on urate handling differed in some species, stopflow studies in the dog indicated the selective inhibition of a ‘secretory peak’ for 14C-labeled uric acid [7]. In contrast, it seemed unlikely (although still remotely possible) that pyrazinamide could result in the enhancement of an active tubular reabsorptive process. Given this background, an attempt was made to roughly estimate urate secretion and reabsorption in normal persons by measuring the maximal decre ment in urate excretion produced by pyrazinamide [36], In order to interpret the results, it was assumed that pyrazinamide results in the virtually complete and selective inhibition of tubular secretion of urate, and also that intrarenal urate secretion and reabsorption do not influence or interfere with one another. Accordingly, the decrement in urate excretion produced by pyrazinamide was interpreted as a minimum estimate of the tubular secretion of urate, while the urinary urate remaining during the action of pyrazinamide was taken to represent the maximum amount of filtered urate that could have escaped tubular reabsorption [36]. This estimate of tubular secretion of urate, the decrement in urate excretion produced by pyrazinamide, varied in a rather direct manner with the plasma urate concentration. In the ten normal persons studied, the plasma urate levels were both raised and lowered through pharma cologic manipulations. The pyrazinamide-induced decrement in excretion always varied directionally with changes in the plasma urate. In addition, over the entire range of plasma urate levels studied, urate reabsorption after pyrazinamide treatment was virtually complete. Those observations suggested that the human kidney normally responds to increased availability of urate, both at the secretory and reabsorptive transport sites, by increasing the rates of bidirectional transport. An increase in the apparent secretory rate appeared to be the primary mechanism whereby urate excretion could increase during hyperuricemia. Accordingly, the results suggested that renal urate homeostasis resides primarily within the secretory system. Similar results subsequently were obtained by G utman et al. [20], As already mentioned, one assumption underlying the interpretation of the ‘pyrazinamide suppression test’ was that pyrazinamide administration causes the selective and effective inhibition of tubular secretion of urate. In contrast, data obtained by F anelli et al. [12] in the Cebus monkey were inter preted as indicating that pyrazinoic acid accelerates the reabsorption of urate.
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
24
25
Subsequent pharmacologic studies in other species, however, have indicated that the antiuricosuric effect elicited by pyrazinamide administration can be attributed to a direct renal action of a metabolite, pyrazinoic acid [37]. In the dog and Cebus monkey, pyrazinoic acid is secreted by renal tubules, probably by the mechanism also secreting hippurates and other organic anions [37]. Furthermore, studies with pyrazinoic acid in the dog [37] and chimpanzee [13] indicated that this compound exerts a dual and ‘paradoxical’ action on renal urate handling. In a manner reminiscent of salicylates and certain other organic anions [43], pyrazinoate at plasma concentrations less than 100 fxg/ml caused a striking antiuricosuric response similar to that which occurs after pyrazinamide administration. At high plasma concentrations, however, pyr azinoate was markedly uricosuric in both species [13,37], This inhibition of urate reabsorption by pyrazinoic acid makes the possibility of accelerated urate reabsorption by pyrazinoate unlikely, in that simultaneous acceleration and inhibition of the same transport mechanism by the same chemical agent would be required. After the administration of the dose of pyrazinamide utilized in the ‘pyrazinamide suppression test’, probably only a small amount of the pyra zinoic acid metabolite is formed; this would serve to inhibit tubular urate secretion rather selectively [37], Nevertheless, a certain small inhibitory action of pyrazinoate on reabsorption cannot be excluded, even at low plasma pyrazinoate levels. In addition, the degree of secretory inhibition occurring during the maximum antiuricosuric action could be incomplete. Thus, the test provides a minimal estimate of urate secretion. Subsequently, certain confusing observations regarding urate handling in disease were reported when the pyrazinamide test was utilized more widely. Hypouricemic patients with Wilson’s disease [38] and Hodgkin’s disease [2], who had elevated urate clearance values, underwent ‘pyrazinamide suppres sion tests’ in attempts to document the site of their inappropriate renal urate loss. To the surprise of most observers, the results suggested inappropriately elevated urate secretion values and normal reabsorption. Whereas renal clear ance values initially were elevated, the urine became virtually urate-free after pyrazinamide administration. The obvious interpretation that disease-induced excessive renal urate losses might stem from inappropriately elevated tubular secretion of urate ran counter to the long accepted notion that such hypou ricemic states probably result from a diminished rate of (proximal) tubular reabsorption of filtered urate as a result of disease-induced tubular lesions. In addition, certain surprising pharmacological observations were re ported. According to the classical formulation in which urate first is filtered,
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
Urate Handling in Normals
S teele/ R ieselbach
then is reabsorbed, and subsequently secreted, the inhibition of tubular sec retion should not affect incremental responses to uricosuric agents. To give an example, the administration of probenecid to a person excreting uric acid at a rate of 400 ¡xg/min could result in a urate excretion rate of 1,400 ¡xg/min, or an incremental response of 1,000 ¡xg/min. After pretreatment with pyrazinamide, baseline urate excretion might be on the order of 50 ¡xg/min, but one would expect the same probenecid-induced incremental uricosuric response of 1,000 ¡xg/min, giving a total urate excretion rate of 1,050 ¡xg/min after both pyrazinamide and probenecid. In contrast, both in the chimpanzee [9] and man [8,35], incremental uricosuric responses to probenecid were virtually abolished by pretreatment with pyrazinamide or pyrazinoate. In addition, the uricosuric responses to intravenous chlorothiazide [35] or aggressive volume expansion with hypertonic sodium chloride [25] were diminished substantially by pretreatment with pyrazinamide. Although the data could have been interpreted as indicating that probenecid, chlorothiazide, and hypertonic sodium chloride infusions all elicited uricosuric responses through a stimulation of the tubular secretion of urate, this interpretation seemed unlikely and even untenable. In contrast to the traditional and rather tacit assumption that urate reab sorption precedes secretion in entirety, recent experiments employing two animal models have indicated that at least some tubular reabsorption of urate may occur coextensively with or following urate secretion in the nephron. In the first micropuncture study of urate handling by the rat kidney in which tubular fluid urate was determined by a microchemical method, the ‘fraction of filtered urate remaining’ at the late proximal tubule substantially exceeded the amount filtered, indicating net secretion of urate by proximal tubules of superficial nephrons in the rat kidney [15]. Yet, simultaneous whole-kidney urate clearances were far less than the glomerular filtration rate [15]. Assuming that the values obtained in superficial nephrons reflected the kidney as a whole, substantial reabsorption of urate must have occurred following its secretion. In subsequent studies in the rat, the net accumulation of urate in proximal tubular fluid appeared to result from a rapid secretory influx of urate across proximal tubular epithelium which was not counterbalanced by equally rapid efflux [23,24]. However, an animal model utilizing a species more closely resembling man would have been more satisfying. In recent years, the chimpanzee has proved to be such an animal model, with physiologic and pharmacologic reactivity analogous to man insofar as renal urate handling is concerned [9,10]. In the chimpanzee, under control clearance conditions, urate excretion normally is far less than the amount
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
26
27
filtered. Yet, after administration of mersalyl, net secretion of urate was clearly demonstrable [11], Indeed, the magnitude of secretion was surprising; urate clearances achieved values nearly double the glomerular filtration rate on occasion [11], The fact that the inhibition of urate reabsorption by mersalyl in the chimpanzee led to the demonstration of such high values of net urate secretion, indicated that the magnitude of intrarenal urate secretion normally must be far greater than the amount excreted. The ‘unmasking’ of extensive urate secretion in the chimpanzee occurred through the inhibition of urate reabsorption by mersalyl, implying that a substantial amount of secreted urate normally is reabsorbed in that species. This reabsorption of secreted urate could occurcoextensively with secretion, as suggested by the bidirectional urate tracer flux studies in the rat proximal tubule [23], or alternatively could occur discretely at sites distal to those where tubular secretion of urate takes place. The discrimination between these two possibilities has not yet been ac complished. The concept of postsecretory urate reabsorption can be utilized to explain suppression of the uricosuric responses to various pharmacologic agents upon inhibition of tubular secretion of urate with pyrazinamide. If the tubular secretion of urate is great in magnitude, then postsecretory reabsorption also must be of a similar or greater order of magnitude, since the amount of urate excreted in man normally is less than 12% of the amount filtered. If post secretory reabsorption were inhibited by a pharmacologic agent or partially impaired by a disease process, it is easy to visualize how the inhibition of tubular secretion of urate (with pyrazinamide) could ablate the uricosuric state. By inhibiting tubular secretion, less urate would be delivered to post secretory reabsorptive sites. Under those conditions, urate might be almost completely extracted from tubular fluid, despite pharmacologic transport inhibition or damage to transport mechanisms by disease. Alternatively, if it is assumed that extensive urate reabsorption occurs prior to any secretion in the nephron, then the inhibition of presecretory reabsorption by drugs or disease would increase the amount of urate delivered distally. Both filtered urate escaping reabsorption and urate derived from tubular secretion would be delivered to postsecretory sites. Depending on the transport characteristics of the postsecretory site, inhibition of urate secretion by pyrazinamide might decrease the load sufficiently to enable virtually complete reabsorption. Thus, it is conceivable that a pharmacologic agent eliciting a uricosuric response which is suppressible by pyrazinamide might act to inhibit urate reabsorption either at presecretory or postsecretory reabsorptive sites, or both. The above formulations depend upon the existence of presecretory reab
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
Urate Handling in Normals
28
S teele/R ieselbach
sorption in a substantial amount. Based on work in the chimpanzee it has been suggested that the presecretory reabsorption may not occur at all [13] but that tubular secretion may be the initial transport event, accompanied or followed by coextensive or postsecretory reabsorption. On teleological grounds alone, this formulation is unattractive because it permits the accumu lation of large amounts of urate in tubular fluid, thereby accentuating the danger of intraluminal uric acid precipitation. This situation could have especially serious consequences in man and other species devoid of uricase, in whom uric acid is the end product of purine degradative metabolism. Recent experiments in man have addressed the particular question of the existence of presecretory reabsorption. In those studies, normal persons were simultaneously treated with pyrazinamide and yeast RNA over a period of several days in order to significantly elevate their plasma urate concentrations, and then underwent renal clearance studies at hyperuricemic plasma urate levels [21]. Irrespective of the level of the plasma urate concentration, the fractional reabsorption of urate after pyrazinamide pretreatment always exceeded 98% of the filtered load [21]. Those data indicate that, in the absence of tubular secretion (inhibited by pyrazinamide), urate reabsorption is ex tremely extensive. In contrast, when urate secretion presumably is intact, it is well known that urinary uric excretion increases greatly during the hyper uricemia accompanying RNA loading [36]. Thus, it seems likely that com bined magnitude of presecretory plus postsecretory reabsorption is far greater that that of postsecretory reabsorption alone.
Unanswered Questions and Possible Directions for Future Research
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
In this review, we have attempted to summarize the many stages through which our present concepts of renal urate handling in man (and several other animal species) have evolved. Indeed, it is apparent that many questions remain unresolved. For example, the existence of postsecretory reabsorption in man could explain many of the rather surprising results obtained utilizing the ‘pyrazinamide suppression test’ in certain disease entities. Nevertheless, direct evidence for postsecretory reabsorption has been obtained only in animal models. To date, no animal model studied exhibits all the character istics of renal urate handling in man. Preferably, any animal model should resemble man as closely as possible. Clearly the rabbit seems to reflect the human condition poorly, for that ‘hypouricemic’ species contains uricase and, in addition, excretes large
Urate Handling in Normals
29
amounts of urate relative to the amount filtered [27], The Dalmatian, an animal with a renal reabsorptive defect for uric acid, also contains uricase in an apparently inaccessible form - possibly reflecting a hepatic transport defect analogous to its renal reabsorptive defect [44], The rat, an animal long favored for laboratory experimentation for economic and other reasons, has been used extensively in recent studies of urate handling [1,6,15,22-24], Although the rat demonstrates substantial intrarenal urate secretion, as well as extensive postsecretory urate reabsorption, it is presently unclear to what extent the intrarenal synthesis of urate contributes to these phenomena [30], Likewise, the mongrel dog has some of the same disadvantages, in that it is a species with both intrarenal urate synthesis [31] and uricase. The Cebus monkey has been ammenable to both classical clearance [12,34] and micropuncture [32] methodologies for the exploration of its renal urate handling. The Cebus monkey has considerable attributes for this type of study, in that its uricosuric responses to many pharmacologic agents are similar to those obtained in man [34], On the other hand, S im k in [33] has shown that the Cebus monkey is a marked overproducer of uric acid, and that its relatively normal plasma urate concentrations (in the presence of uricase) reflect an increased uric acid production and turnover rate. Moreover, the Cebus monkey, like the mongrel dog and rabbit, displays certain dissimilarities to man with respect to organic anion handling. While it appears that hippurates and urate can compete for common secretory transport pathways in the Cebus monkey [12], the mongrel dog [28], rabbit [27], and rat [6,22], recent studies have indicated that this is unlikely in man [5] and the chimpanzee [9], where p-aminohippurate and urate secretion probably occur independently of one another. Finally, the chimpanzee might be the ideal representation of man in a lower species. Indeed, W einer and F anelli have published data in this symposium, from studies employing allopurinol infusion, which indicate that intrarenal urate synthesis cannot be an important factor regulating the minute-to-minute urate excretion in the chimpanzee. Unfortunately, the chimpanzee exhibits one very notable difference in urate handling when compared to man. Although mersalyl administration in the chimpanzee results in the net se cretion of uric acid [11], this may reflect a tendency of that species toward hyperresponsiveness to uricosuric agents [10]. The administration of the same dose of this mercurial to man elicits a more modest uricosuric response which falls far short of demonstrating net secretion1 [F a n elli ]. Thus, to date, no animal model studied totally reflects renal urate handling in man.
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
1 Added in proof: F anelli, G .M .; H itzenberger, G .: Uricosuric activity of intravenous mersalyl in man. Medikon Internat. 30-4: 2 (1974).
30
S teele /R ieselbach
It should be apparent from the above considerations, that our under standing of urate transport in man is incomplete. Currently, it appears that man is the ideal species for the study of at least some aspects of urate transport because results from other species may not be applicable. For example, the detailed study of certain defects in urate reabsorption in man could very likely enhance our knowledge of normal renal urate handling. On the other hand, in order to genuinely advance knowledge through study in man, new ap proaches in methodology presently are needed. Whether such approaches will be pharmacological or more direct remains to be seen. However, it is likely that appropriate investigational techniques ultimately will answer many of the remaining questions in this field. These answers should be relevant to the many unresolved problems related to abnormal urate homeostasis. Some of these clinical problems will be considered in detail in subsequent contributions to this symposium. References
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
1 A bramson, R. G. ; K atz, J. H. ; M aesaka, J. K., and Levitt, M. F. : Uric acid transport in rat kidney. Proc. amer. Soc. clin. Invest, la (1973). 2 Bennet, J.S.; Bond , J.; Singer , I., and G ottlieb, A.V.: Hypouricemia in Hodgkin’s disease. Ann. intern. Med. 76: 751-756 (1972). 3 Berglund , H. and F risk, A. R. : Uric acid elimination in man. Acta med. scand. 86: 128-135(1935). 4 Berliner, R. W. ; H ilton, J. G. ; Yil, T.-F., and K ennedy, T. J., jr. : The renal mechanism for urate excretion in man. J. clin. Invest. 29: 396-401 (1950). 5 Boner, G. and Steele, T. H. : Relationship of urate and p-aminohippurate secretion in man. Amer. J. Physiol. 225: 100-104 (1973). 6 Boudry, J. F. : Effet d’inhibiteurs des transports transtubulaires sur l’excrétion rénale d’acide urique chez le rat. Pflügers Arch. ges. Physiol. 328: 279-291 (1971). 7 D avis, B.B.; F ield , J.B.; R odnan, G .P., and K edes, L.H .: Localization and pyrazinamide inhibition of distal trans-tubular movement of uric acid-2-14C with a modified stop-flow technique. J. clin. Invest. 44: 716-721 (1965). 8 D iamond, H. S. and P aolino, J. S. : Evidence for a post-secretory rcabsorptive site for uric acid in man. J. clin. Invest. 52: 1491-1499 (1973). 9 F anelu , G. M.,jr. ; Bohn , D., and R eilly, S.S. : Renal urate transport in the chimpanzee. Amer. J. Physiol. 220: 613-620 (1971). 10 F anelu , G. M., jr. ; Bohn, D. L., and R eilly, S. S. : Renal effects of uricosuric agents in the chimpanzee. J. Pharmacol, exp. Ther. 177: 591-599 (1971). 11 F anelu , G .M .; Bohn, D .L .; R eilly, S.S., and W einer, I.M .: Effects of mercurial diuretics on renal transport of urate in the chimpanzee. Amer. J. Physiol. 224:985-992 (1973). 12 F anelli, G. M., jr. ; Bohn , D.L., and Stafford, S. : Functional characteristics of renal urate transport in the Cebus monkey. Amer. J. Physiol. 218: 627-636 (1970).
31
13 F anelli, G.M ., jr. and W einer, I.M .: Pyrazinoate excretion in the chimpanzee. Relation to urate disposition and the actions of uricosuric drugs. J. clin. Invest. 52: 1946-1957(1973). 14 F orster, R .P .: Renal transport mechanisms. Fed. Proc. 26: 1008-1019 (1967). 15 G reger, R.; L ang , F., and D eetjen, P .: Handling of uric acid by the rat kidney. I. Microanalysis of uric acid in proximal tubular fluid. Pflügers Arch. ges. Physiol. 324: 279-287(1971). 16 G utman, A. B.: Significance of the renal clearance of uric acid in normal and gouty man. Amer. J. Med. 37: 833-838 (1964). 17 G utman, A. B. and Y ü, T .-F. : 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. Amer. J. Med. 23: 600-622 (1957). 18 G utman, A.B. and YÜ, T.-F.: A three-component system for regulation of renal ex cretion of uric acid in man. Trans. Ass. amer. Physicians 74: 353-365 (1961). 19 G utman, A.B.; YÜ, T.-F., and Berger, L.: Tubular secretion of urate in man. J. clin. Invest. 38: 1778-1781 (1959). 20 G utman, A.B.; YÜ, T.-F., and Berger, L.: Renal function in gout. HI. Estimation of tubular secretion and reabsorption of uric acid by use of pyrazinamide (pyrazinoic acid). Amer. J. Med. 47: 575-592 (1969). 21 J enkins, P. and R ieselbach, R .E .: Unique characteristics of the mechanism for reab sorption of filtered versus secreted urate. Proc. amer. Soc. clin. Invest. 36a: (1974). 22 K ramp, R.W .; Lassiter, W.E., and G ottschalk, C.W.: Urate-2-14C transport in the rat nephron. J. clin. Invest. 50: 35-48 (1971). 23 L ang, F .; G reger, R., and D eetjen, P .: Handling of uric acid by the rat kidney. II. Microperfusion studies on bidirectional transport of uric acid in the proximal tubule. Pflügers Arch. ges. Physiol. 335: 257-265 (1972). 24 Lang , F.; G reger, R., and D eetjen, P.: Handling of uric acid by the rat kidney. III. Microperfusion studies on steady state concentration of uric acid in proximal tubule. Consideration of free flow conditions. Pflügers Arch. ges. Physiol. 338: 295-302 (1973). 25 M anuel, M. A. and Steele, T. H .: Pyrazinamide suppression of the uricosuric response to sodium chloride infusion. J. Lab. clin. Med. 83:417-427 (1974). 26 M ayrs, E. G .: Secretion as a factor in elimination by the bird’s kidney. J. Physiol., Lond. 58: 276-284 (1924). 27 M öller, J.V.: The relation between secretion of urate and p-aminohippurate in the rabbit kidney. J. Physiol., Lond. 192: 505-517 (1967). 28 N olan, R.P. and Foulkes, E. C .: Studies on renal urate secretion in the dog. J. Pharma col. exp. Ther. 179: 429-437 (1971). 29 Praetorius, E. and K irk , J. E .: Hypouricemia: with evidence for tubular elimination of uric acid. J. Lab. clin. Med. 35: 856-868 (1950). 30 Q uebbemann, A .J.: Renal synthesis of uric acid. Amer. J. Physiol. 224: 1398-1402 (1973). 31 Q uebbemann, A. J. and C umming, D .: Renal synthesis of uric acid in isolated perfused dog kidneys. Abstr. amer. Soc. Nephrol. 6: 85 (1973). 32 R och -R amel, F. and W einer, I . M.: Excretion of urate by the kidneys in Ccbus monkeys. A micropuncture study. Amer. J. Physiol. 224: 1369-1974 (1973). 33 Simkin , P. A .: Uric acid metabolism in Cebus monkeys. Amer. J. Physiol. 221:1105-1109 (1971).
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
Urate Handling in Normals
32
S teele/R ieselbach
Request reprints from: T homas H. Steele, MD, 1300 University Avenue, Madison, W153706 (USA)
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:47:25 PM
34 Skeith , M. D. and H ealey, L. A .: Urate clearance in Cebus monkeys. Amer. J. Physiol. 214: 582-584 (1968). 35 Steele, T. H. and Boner, G .: Origins of the uricosuric response. J. clin. Invest. 52: 1368-1375 (1973). 36 Steele, T. H. and R ieselbach, R. E .: The renal mechanism for urate homeostasis in normal man. Amer. J. Med. 43: 868-875 (1967). 37 W einer, I.M. and T inker , J.P.: Pharmacology of pyrazinamide: metabolic and renal function studies related to the mechanism of drug-induced urate retention. J. Pharmacol, exp. Ther. 180: 411-434 (1972). 38 W ilson, D. M. and G oldstein, N. P .: Renal urate excretion in patients with Wilson’s Disease. Kidney Int. 4: 331-336 (1973). 39 Yi), T.-F.; Berger, L., and G utman, A.B.: Renal function in gout. II. Effect of uric acid loading on renal excretion of uric acid. Amer. J. Med. 3 3 :829-844 (1962). 40 Y u, T .-F.; Berger, L., and G utman, A. B.: Suppression of tubular secretion of urate by pyrazinamide in the dog. Proc. Soc. exp. Biol. Med. 107: 905-908 (1961). 41 Yu, T.-F.; Berger, L.; K upfer , S., and G utman, A.B.: Tubular secretion of urate in the dog. Amer. J. Physiol. ¡99: 1199-1204 (1960). 42 Yu, T.-F.; Berger, L.; Stone, D .J.; W olf, J., and G utman, A.B.: Effect of pyrazin amide and pyrazinoic acid on urate clearance and other discrete renal functions. Proc. Soc. exp. Biol. Med. 96: 264-267 (1957). 43 Yu, T.-F. and G utman, A.B.; A study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanism for excretion of urate in man. J. clin. Invest. 38: 1298-1315 (1959). 44 Yu, T.-F.; G utman, A.B.; Berger, L., and K aung, C .: Low uricase activity in the dalmatian dog simulated in mongrels given oxonic acid. Amer. J. Physiol. 220:973-979 (1971).
