THE RENALEXCRETIONOF URIC ACID IN PATIENTS WITHGOUTAND IN NONGOUTYSUBJECTS* t

By C. A. NUGENTAND F. H. TYLER(From the Department of Medicine and the Laboratory for the Study of Hereditary and

Metabolic Disorders, University of Utah College of Medicine,Salt Lake City, Utah)

(Submitted for publication April 1, 1959; accepted July 6, 1959)

The elevation of the plasma uric acid concentra-tion in patients with gout has been attributed byvarious authors to: a) decreased destruction ofuric acid, b) overproduction of uric acid, or c)an abnormality in the renal excretion of uric acid(1). Decreased destruction of uric acid in pa-tients with gout has not been found in studiesutilizing labeled uric acid (2). A metabolic ab-normality in the production of uric acid has beendemonstrated in some patients with gout; how-ever, increased production of uric acid has notbeen a uniform finding (3, 4).

The possibility that there might be a specificabnormality in the renal excretion of uric acid bypatients with gout has been investigated on numer-ous occasions. The most extensive recent investi-gations of the renal excretion of uric acid werecarried out by Coombs and co-workers (5), Tal-bott (6) and Gutman and Yu (1), all of whomagreed that there is no essential difference in themanner in which uric acid is excreted by subjectswith gout and by normal subjects. However, theirstudies were performed while the normal subjectsand gouty patients had markedly different plasmauric acid concentrations. In the present investiga-tion of the renal excretion of uric acid, patientswith gout were studied under control conditionsand nongouty subjects were studied before andafter they had been given uric acid or its pre-cursors in amounts great enough to elevate theirplasma uric acid concentrations to values com-parable to those of the gouty patients.

METHODS

Six male patients with gout were studied. One patientwas studied on two occasions. Their clinical status is

* Presented in part at the Western Society for ClinicalResearch, January, 1959, Carmel, Calif.

t This work was supported by Grants A-2 and A-1828from the National Institute of Arthritis and MetabolicDiseases, National Institutes of Health, United States.Public Health Service, Bethesda, Md.

indicated in Table I. In every case, a typical history ofacute gouty arthritis was obtained. Gouty patients withrenal failure, heart disease or advanced age were pur-posely excluded from the study. Ten studies were per-formed on seven nongouty male subjects. The clinicalinformation on this group is also given in Table I.

The control studies were carried out while all of thegouty patients and nongouty subjects were taking theirusual diets. They were instructed, however, to eat nohigh purine foods and to take no uricosuric drugs for atleast one month before the studies. The test studies weredone after the nongouty subjects had been given uricacid or one of its precursors in addition to their diet.The nature of these dietary supplements is indicated inTable I. Two nongouty subjects were studied after theyhad been fed a high purine diet. The high purine dietwas isocaloric with the control diet and contained thesame proportions of fat, carbohydrate and protein, butsardines, liver and anchovies were used to provide 90per cent of the protein. All of the remaining subjectswere given ribose nucleic acid packed in gelatin capsulesand administered in four equal doses with meals and atbedtime. One normal subject was also given uric acidand desoxyribose nucleic acid. With one exception, eachsubject received the dietary supplement for a three dayperiod. On the morning of the fourth day, three hoursbefore the first clearance period, the subjects were giventheir usual morning dose of the dietary supplements.The two subjects on the high purine diet, however, re-ceived no food before the renal function studies on thefourth day. Subject 7 was given ribose nucleic acid forfive days and after his usual morning dose of ribose nu-cleic acid the renal function studies were repeated on thesixth day.

All the studies were started between 7:00 and 8:00 a.m.and completed between 10:00 a.m. and 12:00 noon. Thesubjects were hydrated by the oral administration of 600to 800 ml. of water in the first hour and 150 to 250 ml. ofwater every half hour during the remainder of the study.Standard clearance methods were used (7). Catheteriza-tion of the bladder, however, was done only in those casesin which the estimated residual bladder urine exceeded20 ml. (8). The urine collection periods varied from 10to 20 minutes in the catheterized patients and 15 to 30minutes in the voiding patients. All clearances in thisreport represent the average of the values from two tofour sequential clearance periods. Two to four plasmaspecimens were analyzed during each study. The indi-vidual inulin clearances did not vary more than 10 per

1890

RENALEXCRETIONOF URIC ACID

TABLE I

Clinical data and dietary regimens

FamilyPatients Age SA* Regiment Catheterized$ history Tophi Arthritis

yTS. M.2 yrs.Nongouty subjects

1 40 1.76 High purine 0 0 0 02 26 1.70 High purine 0 0 0 03A 47 1.75 4 Gm. RNA 0 0 0 03B 4Gm. RNA 0 0 04A 37 1.85 4 Gm. RNA 0 0 0 04B 4 Gm. DNA 04C 4 Gm. UA 05 23 1.92 4 Gm. RNA 0 0 0 06 51 1.74 4 Gm. RNA 0 0 0 07 23 1.85 7 Gm. RNA 0 0 0 0

Patients with gout8 55 2.0 0 0 0 0 109 52 1 73 0 + + 0 5

10 49 1.82 0 + + 0 1011 44 1.85 0 0 + + 112 28 2.1 0 0 0 0 413A 51 2.2 0 + 0 0 613B 0 +

* SA = surface area.t RNA= ribose nucleic acid, DNA= desoxyribose nucleic acid, UA = uric acid.t A "+" sign in this column indicates that the individual was catheterized during the renal function study.

cent from the mean of the particular study with fourexceptions. In these four studies, the uric acid to inulinclearance ratios for the individual periods did not varymore than 5 per cent from the mean of the particularstudy.

Blood specimens were mixed with heparin and theplasma was separated by centrifugation. The enzymatic 1

spectrophotometric method of Praetorius was used for thedetermination of uric acid (9). The plasma uric acid de-terminations reported here were performed directly onthe specimens without prior protein precipitation. Inaddition, enzymatic spectrophotometric uric acid deter-minations were done on protein-free filtrates of plasmaprepared by the method of Forsham, Thorn, Prunty andHills (10). None of the urine specimens contained pro-tein by the heat and acetic acid test. The uric acid de-terminations were carried out directly on diluted urinespecimens. Inulin was determined by the method ofYoung and Raisz (11). The anthrone precipitated whenused in the concentrations suggested by these authors.Their method worked satisfactorily, however, with 3.2Gm. of anthrone in place of the recommended 4 Gm. perL. of acid solution and 1.25 ml. of unknown solution inplace of the recommended 2 ml. of unknown per 10 ml. ofanthrone solution (12). Twenty-four hour urine collec-tions were obtained during the control period and on thelast day of each oral loading period. The method ofPhillips (13) was used for urine creatinine determinations.

1 The uricase was obtained through Worthington Bio-chemical Corporation, Freehold, N. J.

RESULTS

The results of the renal function studies (TableII) have been corrected to a body surface area of1.73 M.2. No correction was made for the re-sults of the 24 hour urine collections. One non-gouty subject had an average inulin clearance of82 ml. per minute. The history, physical examina-tion, urinalysis and intravenous pyelogram onthis subject were all within normal limits. Oneadditional nongouty subject and four of the goutypatients had inulin clearances below 100 ml. perminute. In no case, however, was the inulinclearance outside the range of variation for theage or more than two standard deviations belowthe mean of the subjects studied by Davies andShock (14).

The mean plasma uric acid concentration was5.6 mg. per 100 ml. in the nongouty subjects and9.2 mg. per 100 ml. in the gouty patients undercontrol conditions. Two of the nongouty subjectshad plasma uric acid concentrations of 7.1 and 7.2mg. per 100 ml. In our laboratory, using freshwhole plasma, uric acid concentrations of thislevel are occasionally seen in normal subjects.These values exceed what is usually considered

1891

C. A. NUGENTAND F. H. TYLER

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RENAL EXCRETION OF URIC ACID

the upper limits of the normal range of uric acidin protein-free serum filtrates (1). Other in-vestigators have also noted the slightly higheruric acid values obtained with enzymatic spectro-photometric methods on whole plasma (15).

The mean uric acid clearance and proportion offiltered uric acid excreted by the patients withgout was slightly lower and the mean filtered, re-absorbed and excreted uric acid was slightly higherthan in the nongouty subjects (Table II and Fig-ure 1). There was some overlap of individualvalues between the two groups of subjects in everymeasured parameter with the exception of theplasma uric acid concentration. The mean 24hour urine uric acid excretion was higher in thepatients with gout than in the nongouty group.One patient with gout excreted 1,090 mg. of uricacid per day. All of the other patients with goutfor whomwe have data excreted between 465 and617 mg. of uric acid per day, which is approxi-mately the same range as that of the nongoutysubjects. In view of the difficulty of collecting 24hour urine specimens on nonhospitalized subjects,uric acid to creatinine ratios were determined.These were similar in the two groups under con-trol conditions. That the majority of subjectswith gout do not excrete an abnormally largeamount of uric acid each day in their urine isshown by our data and in the extensive investiga-tions reported by Gutman and Yu (1).

Daily administration of 4 Gm. of uric acid bymouth had little effect on the plasma uric acid con-

-I0

E 200 PUA FUA CA UCAIN A

150 UNGGG-

0,0

G-G NGG NGG NGG NGG

FIG. 1. RENAL FUNCTION OF NONGOUTYSUBJECTS(NG) AFTER ORAL LOADING WVITH PURINES COMPAREDWITH THAT OF PATIENTS WITH GOUT (G) UNDERCONTROLCONDITIONS

The height of each column represents the mean resultsexpressed as per cent of the nongouty control values.PUA= plasma uric acid concentration, FLA_ filtered uricacid load, CUA= uric acid clearance, CIN = inulin clear-ance and UUAV= rate of uric acid excretion.

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FIG. 2. THE RELATION OF TUBULAR REABSORPTIONOF URIC ACID (TUA) TO FILTERED URIC ACID LOAD(FUA)

The heavy diagonal line indicates total reabsorption ofthe filtered load of uric acid. The results of the studieson the nongouty subj ects under control conditions areindicated by open circles and after uric acid loading bysolid circles. The values in the patients with gout stud-ied under control conditions are indicated by cross marks.

centration or the 24 hour urine urate excretion.2The high purine diet and 4 Gm. per day ofdesoxyribose nucleic acid were moderately effec-tive while 4 Gm. per day of ribose nucleic acidusually resulted in a striking rise in plasma uricacid concentration and in 24 hour urine uric acidexcretion. The greatest increase in plasma uricacid concentration occurred in the subject whowas given 7 Gm. of ribose nucleic acid per day for

2 In Study 4c, after 4 Gm. of uric acid a day for threedays, the plasma uric acid concentration was 6.4 mg. per100 ml. and the filtered uric acid 7.9 mg. per minute.These values differed little from the plasma uric acidconcentration and filtered uric acid load of the controlstudies and were far below the levels of the patients withgout. Therefore, the results of the 4c study are not in-cluded in Table II but are plotted in Figures 2, 3 and 4.No control studies were done immediately before theoral administration of uric acid in the case of 4c, but theresults of the 4A and 4B control studies were very similarto one another and therefore have been used as a baseline.It can be seen that the changes after oral uric acid, al-though slight, were in the same direction as those inducedby the other dietary supplements. Four Gm. of uric acida day in other subjects induced similar changes in plasmaand urine uric acid.

1893

C. A. NUGENTAND F. H. TYLER

FUA mg./min.

FIG. 3. THE RELATION OF THE PROPORTION OF FIL-TERED URIC ACID EXCRETED (CUA/CIN) TO THE FIL-TERED URIC ACID LOAD (FUA)

Symbol conventions are the same as in Figure 2. Seetext for discussion.

five days. No investigation was made of the roleof variations in absorption or destruction in thegastrointestinal tract or variations in the degree ofconversion to uric acid in determining the differ-ences between the response to the various dietaryregimens.

High purine intake in the nongouty subjects re-sulted in a rise of the mean plasma uric acid con-centration to 7.9 mg. per 100 ml. Although, underthese conditions, the mean filtered uric acid loadwas almost identical with the control value in thegouty patients, the nongouty subjects excreteduric acid at two times their control rate of excre-tion and their proportion of filtered uric acidexcreted and their uric acid clearance far ex-ceeded that of the gouty patients (Figure 1). Themean 24 hour urine uric acid excretion of the non-gouty subjects rose well above their control leveland exceeded the mean of the gouty patients.

Figure 2, in which renal tubular reabsorption ofuric acid is plotted as a function of filtered uricacid load, reveals no gross difference between thegouty and the nongouty groups. The heavy di-agonal line indicates total reabsorption of thefiltered uric acid. The proportion of the filtereduric acid excreted is indicated by the vertical dis-tance between a point and the heavy line comparedto the vertical distance from the heavy line to thelevel of no reabsorption of uric acid. Some in-vestigators have used similar data, plotted as inFigure 2, to support the notion that the percentageof the filtered load of urate reabsorbed in gout does

not differ from that of normal subjects at equiva-lent filtered urate loads (1). Since only a verysmall proportion of the total filtered urate load isexcreted either by gouty patients or by normalsubjects, a plot of the data in this fashion tends toobscure differences in the proportion of filtereduric acid excreted. When the proportion of thefiltered load of urate excreted (uric acid/inulinclearance ratio) is plotted as a function of filteredurate load (Figure 3), a difference is apparentbetween the nongouty subjects and the patientswith gout. Under control conditions, the propor-tion of filtered uric acid excreted is slightly lowerin the patients with gout than in the nongouty sub-jects. Oral administration of uric acid precursorsto nongouty subjects resulted in the elevation oftheir filtered urate load to the range of those ofthe patients with gout. Under these circumstancesthe nongouty subjects excreted a higher propor-tion of their filtered urate load than did the pa-tients with gout who had comparable filtered loads.All but one of the nongouty subjects excreted ahigher proportion of their filtered load of uricacid during the experimental than during thecontrol periods. The values for two gouty pa-tients in Figure 3 lie in the area occupied by thenongouty subjects under control conditions. Thesetwo individuals, Patients 10 and 12, had the low-est plasma uric acid concentrations of the patientswith gout. In addition, Patient 10 had the lowestinulin clearance among the patients with gout.

In Figure 4, the proportion of filtered uric acidexcreted is plotted as a function of the plasma uric

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FIG. 4. THE RELATION OF THE PROPORTIONOF FiL-TERED URIC ACID EXCRETED (CIUA/CIN) TO THE PLASMAURIC ACID CONCENTRATION(PuA)

Symbol conventions are the same as in Figure 2.

1894

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RENALEXCRETION OFURIC ACID

acid concentration. The same general relationsbetween the two groups shown in Figure 3 can beseen here. The control data of the nongouty sub-jects and gouty patients are better separated in Fig-ure 4 than in Figure 3. Possibly the proportionof filtered urate excreted is a function of theplasma urate concentration rather than of thefiltered load.

The results of the plasma uric acid determina-tions after protein precipitation differed fromthose reported in this paper only in that theplasma uric acid concentrations were 9 per centlower, with a standard deviation of 4 per cent.This resulted in corresponding changes in theamounts of uric acid filtered and reabsorbed andin the uric acid clearance, but the relations be-tween the various values and their appearanceafter plotting showed little difference from the re-sults reported here.

DISCUSSION

It is usually stated that the plasma uric acid iscompletely filterable by the glomeruli, that a vary-ing proportion of the filtered uric acid is reab-sorbed by the renal tubules and that none is ex-creted by the tubules (16). There is considerableexperimental evidence that plasma uric acid iscompletely filterable (17). As judged by thework of one group of investigators, who usedpaper electrophoresis with many different buffersand a wide variety of experimental conditions in-cluding variation in pH, ionic strength, tempera-ture and potential gradients, no inhomogeneity ofthe plasma uric acid has been demonstrated (18).It is not so generally accepted that there is norenal tubular excretion of uric acid in humans.The anomalous decrease in the clearance of uricacid which uniformly occurs after the administra-tion of small doses of a wide variety of agentswhich increase urate clearance at higher doses (1)is one of the facts which is difficult to explain if oneaccepts the view that uric acid is not excreted bythe tubules. However, for convenience, and inthe absence of conclusive evidence that the as-sumptions stated above are not correct, we willaccept them for the purpose of this discussion.

Many investigations of renal function in gouthave been carried out in the past. These have in-cluded study of the effect of feeding uric acidprecursors (19). In these investigations, how-

ever, there has been great variation in the methodsused for measurement of uric acid concentrationand glomerular filtration rate. Because of theirlarge number and the great differences in tech-niques employed, a discussion of all of the reportswill not be presented here. The studies of Coombsand co-workers (5), of Talbott (6) and of Gut-man and Yu (1) were carried out on large num-bers of patients and inulin was used for the de-termination of glomerular filtration rates. In par-ticular, the studies of Gutman and Yu (1) seemmost suitable for comparison with our own. Theseinvestigators corrected for nonurate chromogen inurine by using uricase and demonstrated agree-ment of their colorimetric method with enzymaticspectrophotometric measurements (20). Some ofthe results of Gutman and Yii's studies are shownin Table III for comparison with the data of thepresent investigation.

The results of the renal function studies undercontrol conditions reported here are similar to thefindings of Coombs and associates (5), Talbott(6) and Gutman and Yu (1). The means of theuric acid clearance, proportion of filtered uric acidexcreted and rate of uric acid excretion are onlyslightly different in the nongouty and gouty groupsand there is some overlap of individual values..These findings have led many observers in thepast to conclude that there is no abnormality inthe renal excretion of uric acid by patients withgout (1, 5, 21). Oral purine loading of the non-gouty subjects enabled us to study renal functionin nongouty subjects and in gouty patients at com-parable plasma uric acid concentrations. Underthese conditions, the uric acid clearance, propor-tion of filtered uric acid excreted and rate of uricacid excretion by the nongouty subjects were wellabove the levels observed in the gouty patients.Since the filtered uric acid load of the nongoutysubjects after purine loading was approximatelythe same as that of the gouty patients, the differ-ence in renal excretion of uric acid between thetwo groups must be attributed to a lower tubularreabsorption of uric acid by the nongouty subjects.

The rise in 24 hour urine uric acid excretion inthe nongouty subjects after high purine intake,although large, is not as great as one would expectfrom the doubling of the rate of uric acid excre-tion during the renal clearance studies. Severat

1895

C. A. NUGENTAND F. H. TYLER

TABLE III

Renal function*

Present data

Data of Gutman and uii (1) Nongouty males

Nongouty Uratemales Gout Control load Gout

PUA (mg./100 ml.) 5.6 9.0 5.6 7.9 9.2±41.3 41.4 1.1 41.3 ±1.1

CIN (ml./min.) 98.5 110 114 100±17.7 ±17 ±18 411

CUA (ml./min.) 8.7 7.5 8.5 11.7 6.2±2.5 ±-2.4 ±-1.2 ±-1.9 ±0.8

FUA (mg./min.) 6.3 10.1 6.1 8.9 9.2±1.4 42.8 41.2 ±1.5 ±1.7

TUA (mg./min.) 5.8 9.5 5.6 8.0 8.6±41.4 ±2.6 ±1.1 ±1.4 ±1.6

CUA/CIN 0.076 0.068 0.078 0.104 0.062±0.024 ±-0.021 ±0.014 40.016 ±0.005

UUAV(mg./min.) 0.493 0.663 0.46 0.92 0.57±0.159 ±0.235 ±0.06 0. 1 7 ±0.10

24 Hr. Ur UA (mg.) 418 497 527 926 647±70 (range, 170 ±91 ±-260 ±4227

to 1,520)

* The results are expressedused in Table II.

as the means and the standard deviations. The abbreviations are the same as those

explanations seem plausible. There are manyextraneous factors which influence the excretion ofuric acid. One would expect dietary changes (22,23) and exercise (24, 25) to be more prominentvariables during a 24 hour urine collection periodthan during a renal clearance study. One of theseeffects is strikingly illustrated in Subject 7. Thissubject hiked in mountainous country during theday of his urine collection period after purineloading. The prolonged and striking effect ofexercise in decreasing the excretion of uric acidmay well account for the relatively small increasein 24 hour urine uric acid excretion that wasassociated with a marked rise in plasma uric acidconcentration and rate of uric acid excretion dur-ing the final renal function study in this subject.

The nongouty subjects were fed uric acid or itsprecursors for periods of only three days. It isconceivable that in time the normal subjects wouldhave "adapted" to prolonged elevation of theirplasma uric acid concentration and eventuallywould have excreted a smaller proportion offiltered uric acid. Repeated renal function studieswere done on four nongouty subjects maintained

for periods of one mnonth on 4 to 8 Gm. of ribonu-cleic acid per day (26). There was no significantchange in their renal excretion of uric acid as-sociated with the passage of time.

In the past few years overproduction of uricacid has been regarded by many investigators asthe basis for hyperuricemia in gout (1, 27, 28).The presence of tophaceous deposits around joints,uric acid calculi and large amounts of uric acid inthe urine of some patients with gout led Garrodto conclude that "an undue formation of this sub-stance would favor the occurrence of the disease"(29). However, there are many patients withgout in whom overproduction of uric acid is notreadily apparent. The majority of gouty patientsdo not excrete abnormally large amounts of uratein their urine, many do not have tophi (1), andin some patients without tophi the miscible uricacid pool is only 3 to 5 Gm. (30, 31). The pro-longed increase in urate excretion induced by ad-ministration of uricosuric agents to some patientswith nontophaceous gout suggests that these pa-tients have urate deposits that are not clinicallyobvious (32). The increased incorporation of

1896

RENALEXCRETIONOF URIC ACID

glycine into uric acid demonstrable in some pa-

tients with gout has been regarded as supportingthe overproduction theory as the basis for hyper-uricemia. In discussing overincorporation, Wyn-gaarden makes clear the distinction between earlyoverincorporation of glycine into urinary uric acid,a defect actually demonstrated in some gouty pa-

tients, and overproduction of uric acid. Earlyoverincorporation of glycine and significant over-

production of uric acid are not necessary con-

comitants (28).Regardless of whether overproduction of uric

acid occurs in all patients with gout, the data ofthe present investigation do not support the over-

production theory as the exclusive basis for hyper-uricemia in gout. In the present study, the non-

gouty subjects required oral purines in amountsgreat enough to double their milligram per minuteexcretion rate of urates and far exceed the excre-

tion rate of the gouty patients in order to producehyperuricemia of similar magnitude to that ob-served in the gouty patients. Excluding indi-viduals with renal disease, if the elevation of theserum uric acid in gout were simply due to over-

production of uric acid, then gouty patients shoulduniformly excrete larger than normal amounts ofuric acid in their urine.

It seems very likely that gout is fundamentallythe result of a metabolic abnormality. In view ofthe present facts, however, it does not seem likelythat the hyperuricemia of most patients with goutis solely attributable to overproduction of uric acid.Abnormal renal excretion of uric acid is an im-portant cause of hyperuricemia in some patientswith gout. In addition to the overproduction ofuric acid demonstrable in some patients, a meta-bolic defect in gout might affect the plasma urateconcentration by: a) the production of a nonuratesubstance affecting renal excretion of uric acid andresulting in hyperuricemia; b) the production ofuric acid that was bound to protein or differedfrom the remainder of the plasma uric acid insome other respect; or c) a metabolic defect mightaffect the kidneys in some more direct manner.

Wehave no evidence to support any of these pos-

sibilities.

CONCLUSIONS

1. Renal function studies were performed on

seven nongouty male subjects on 10 occasions and

on six gouty male patients on seven occasionsunder control conditions. The inulin and uric acidclearances, proportion of filtered uric acid excretedand rate of uric acid excretion were similar inthe two groups.

2. Uric acid precursors were administeredorally to the nongouty subjects for three to fiveday periods in order to increase their plasma uricacid concentrations and filtered uric acid loads tothe range found in the patients with gout. Underthese conditions, the nongouty subjects reabsorbeda smaller proportion of their filtered uric acid andachieved a uric acid clearance and uric acid excre-tion rate well above the levels observed in thegouty patients.

3. It is concluded that abnormal renal excretionof uric acid is one important cause of hyper-uricemia in some patients with gout.

REFERENCES

1. Gutman, A. B., and Yii, T. F. Renal function ingout. Amer. J. Med. 1957, 23, 600.

2. Buzzard, J., Bishop, C., and Talbott, J. H. The fateof uric acid in the normal and gouty human being.J. chron. Dis. 1955, 2, 42.

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