J Clin Pathol 1981;34:1245-1254

Uric acid, gout and the kidneyJS CAMERON, HA SIMMONDS

From the Renal Unit and Purine Laboratory, Department of Medicine, Guy's Hospital, London SEJ 9RT

Uric acid is 2,6,8-trihydroxypurine, and seems to bepresent in almost all organisms. In snakes, reptiles,birds and spiders it is the main end-product of allnitrogenous metabolism, and these groups of animalshave kidneys which are capable of secreting largeamounts of uric acid. This is then excreted as aslurry of crystals, which confers the advantage thatthe nitrogenous end-product can be excreted withvery little water, a benefit in arid environments. Incontrast, the excretion of urea necessitates the loss ofa relatively larger quantity of water, the size ofwhich is dependent upon the concentrating ability ofthe kidney.

In mammals, uric acid is the end-product only ofpurine metabolism and is formed by the breakdownof purine nucleotides, which are derived from DNAand RNA, and also from other compounds import-ant in general metabolism, such as ATP, ADP andAMP, FAD, coenzyme A and S-adenosylmethio-nine. In mammals, with the exception of man andclosely related primates, uric acid is further brokendown to allantoin by the enzyme uricase. Theadvantage of this is that allantoin is a very solublecompound, whereas uric acid is very insoluble.At physiological pH only the hydroxyl group at

the 8 position, which has a pK of 5 4, dissociates.Therefore, in blood and tissue fluids uric acid isoverwhelmingly (98%) in the dissociated form ofUr-, so that effectively in tissue fluids the predomin-ant form is Na+Ur-, with smaller amounts ofK+Ur-etc. In the urine, in contrast, as the physiologicalrange of pH is 4-7 to 8-0, the proportion of HUr toUr- varies greatly; in most acid urines the form ispredominantly the undissociated acid. This ismany times less soluble in water than sodium urate,hence the great variation in the capacity of urine ofvarious pHs to dissolve uric acid (Fig. 1).The toxicity of and the pathological changes

caused by uric acid are entirely the consequences ofits insolubility. This would not matter so much,except perhaps for a tendency to form crystals orstones in acid urine, were it not for one otherpeculiarity which primates also display, namely thatthe renal tubule reabsorbs around 90% of thefiltered urate. There is great variation betweendifferent mammals in the renal handling of uric

140

2-

I/

2 4

0.O-10 . .

1.5 50 55 60 65 70pH

Fig. 1 The solubility of the HUr/H+Ur- system inurine, in which the principal cation is Na+.

acid,' from net secretion with uric acid clearancestwo to three times the glomerular filtration rate, asin the pig and some rabbits, down to man, who hasa net reabsorption of uric acid in the renal tubulehigher than any other mammal except closelyrelated primates.The result of the deletion of the enzyme uricase

and the extensive tubular reabsorption of uric acidis that the concentration of uric acid in human bodyfluids is not far off the limit of solubility in plasmaat 37°C (about 0 45 mmol/l), especially in males,who have a higher level of plasma uric acid thanchildren or premenopausal females. This contrastssharply with other mammals whose plasma uricacid is, in general, less than O 03 mmol/l: in the pigit is as low as O0002 mmol/l. The evolutionaryadvantage of this production and retention of uricacid is not clear, especially as it carries with it therisk of gouty disease.

Handling of uric acid by the kidney

Urate is handled by the human kidney in a complexfashion which has a number of clinically important

1245

copyright. on M

arch 12, 2020 by guest. Protected by

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.34.11.1245 on 1 N

ovember 1981. D

ownloaded from

C1c6meron, Simmonds

consequences.2 It includes filtration, followed by abidirectional tubular transport system involving re-absorption, secretion and finally postsecretory re-absorption (Fig. 2). The exact sites of these trans-port systems within the nephron are not known, andthey may coexist extensively throughout the proxi-mal tubule. It is likely that the brief account givenhere will have to be changed in the future.

8-10

Fig. 2 Cur-rent concepts of the handling of ur-ate bhthe human renal tubule. The numbers represent theamount of iurate handled as a percentage of the filteredload.

Plasma proteins, principally albumin, are capableof binding uric acid, but the extent of such bindingis uncertain in human plasma at 37°C. Binding,however, appears appreciable at 4°C; this is re-

sponsible for frequent statements in the past thaturic acid is extensively bound (ca 15 0), and there-fore not freely available for filtration. Currentevidence suggests that the contrary is true underphysiological circumstances in man, and thatvirtually l00% of plasma urate may be filtered atthe glomerulus.

Calculations suggest that some 50 mmol of urateare filtered at the glomeruli in a normal adultevery 24 h; yet less than 4 mmol/day are excretedafter several days on a purine-free diet, and rathermore on a higher purine intake. Net reabsorptionis about 90% in females, and 92% in males;3 thisdifference accounts for the higher plasma uric acidin males and is perhaps influenced by sex hormones.It is necessary to postulate only filtration and re-

absorption to account for these data, but observa-tions of uric acid clearances in excess of the glom-

erular filtration rate in individuals with inherited oracquired renal tubular defects as well as in healthyindividuals during urate loading coupled withprobenecid treatment (a uricosuric agent), made itnecessary to postulate tubular secretion as well.At one time it was assumed that almost all the

filtered urate was reabsorbed, and that urinaryurate arose almost entirely from a postreabsorptivesecretory mechanism. The principal evidence forthis suggestion came from studies using the anti-tuberculous agent pyrazinamide (PZA) which, in itsactive form pyrazinoic acid, almost completelyabolishes urinary excretion of urate in man reducingit to 05% of filtered urate even in the face of apurine load. This leads to a sharp rise in plasmaurate which limits the use of the drug therapeutically.Studies in some other species showing net secretionof urate-for example, the Dalmatian dog, suggestedthat PZA acted purely by blocking tubular secretionof urate, and this was assumed to apply to man withthe additional assumption that secretion of urate inthe nephron occurred at a site distal to the re-absorptive site.More recent data have necessitated further

modification of this "three component" filtration-reabsorption-secretion model of urate handling.There is increasing evidence to suggest that at leastsome of the tubular reabsorption occurs at a sitedistal to the secretory site.4 Thus, studies of theeffect of PZA in patients with tubular disease and anabnormally high excretion of urate (see below)showed, surprisingly, that the drug all but abolishedurate excretion in these individuals, just as innormal subjects. PZA was also found to bluntconsiderably the response to uricosuric agents, suchas probenecid, in healthy individuals. These observa-tions are most plausibly explained by supposing thatmore urate is secreted than is suggested by sup-pression with PZA alone, and that some of thissecreted urate also is reaborbed more distally in thenephron. The data suggest further that the uricosuricdrugs, or tubular disease, affect this distal reabsorp-tive site predominantly.A further doubt has been thrown on the signifi-

cance of estimates of the tubular secretion of urateusing PZA by the observation that, in primates, athigh plasma drug concentrations (> 100 [tg/ml)PZA is uricosuric, apparently decreasing reabsorp-tion, rather than exerting its predominant effect ofdecreasing secretion at lower concentrations. In thisrespect, PZA resembles a number of other drugsaffecting urate excretion (see below).The present picture of urate handling in the

nephron is summarised in Fig. 2. Approximately100%0 of plasma urate is filtered, and almost all of itis reabsorbed at a proximal site. Secretion then

1 246

copyright. on M

arch 12, 2020 by guest. Protected by

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.34.11.1245 on 1 N

ovember 1981. D

ownloaded from

Uric acid, gout and the kidney

occurs, equivalent to about 50% of the filtered urate,and 80% of this is reabsorbed at a more distal site,probably still within the proximal tubule. Thus, anamount of urate is finally excreted which approxi-mates to only 10% of the filtered load.A large number of factors affect the renal handling

of urate. Displacement of urate from albumin is nolonger thought to be of importance, but a number ofphysiological and pathological agents are capable ofreducing urate excretion, and hence causing a rise inplasma urate (Fig. 3). Any of these, therefore, maylead to an acute attack of gout in a susceptibleindividual whose plasma urate concentration isalready marginally raised. Several of these deservecomment. The best known of the physiologicalsubstances are organic acids such as lactate whichinterfere with tubular handling of urate; their

1247

overproduction may explain in part the hyperuri-caemia associated with alcohol intake, with statusepilepticus and with starvation. Diuretics causeplasma volume contraction, and fractional uratereabsorption increases under these circumstances, asdoes Na+ and HC03- reabsorption. A number ofdrugs which increase the excretion of urate at highdoses decrease the excretion at low doses. Alluricosuric agents so far studied exhibit this biphasicresponse (except benzbromarone), but the agentwhich is best known for this property is aspirin,because its effect changes from reduced excretion toincreased excretion of urate within its therepeuticrange. For most other agents except PZA the changeoccurs well below the usual dose, so that retentionof urate is not usually observed. It can be postulatedthat this biphasic action is the result of differential

RENAL EFFECTS PLASMA URATE

Fig. 3 A summary offactors tending to diminish net urate excretion so that a rise in plasma urateconcentration follows.

copyright. on M

arch 12, 2020 by guest. Protected by

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.34.11.1245 on 1 N

ovember 1981. D

ownloaded from

Cameron, Simmonds

effects on secretion and postsecretory reabsorptionof urate. Benzbromarone appears to be unique inthat, unlike the other agents, it is not itself carried bythe proximal tubular organic acid transport system,and therefore does not itself compete directly withthe urate for whatever carrier is present. Chronic leadintoxication leads to a decrease in urate excretion byan undetermined mechanism;5 renal failure is aprominent and early manifestation, but arthritis("saturnine" gout) is usually mild.

Those circumstances which lead to an increase ofurate excretion and a fall of plasma urate are shownin Fig. 4. The most important of these are the groupof uricosuric drugs. On occasion the excretion of

urate following their administration may be so greatas to lead to acute renal failure, through precipita-tion of urate in the tubules as was observed in somepatients treated with the uricosuric diuretic tienilicacid (Ticrynafen).6 Circulatory volume expansiontends to increase urate excretion, and such expansion

for example, brought about by the inappropriatesecretion of ADH, may explain some of the hypouri-caemias seen occasionally in patients with malignantdisease. Massive doses of vitamin C are uricosuricand may lead to renal colic. Other agents notnormally thought of as affecting urate excretionalso lead to considerable uricosuria, including mostradiocontrast media, warfarin and corticosteroids.

RENAL EFFECTS PLASMA URATE

Anti -coagulant Ra[iocontrLstge

I Anti-inflammatory agents

Fig. 4 A summary offactors tending to increase net urate excretion so that a fall in plasmaurate concentration follows.

1248

copyright. on M

arch 12, 2020 by guest. Protected by

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.34.11.1245 on 1 N

ovember 1981. D

ownloaded from

Uric acid, gout and the kidney

Uric acid In renal diseases

TUBULAR DISEASEIt is worth mentioning first the rare abnormalitiesof renal tubular urate handling. Several familieshave been described with an isolated defect oftubular reabsorption of urate, in whom the clearanceof urate may exceed the glomerular filtration rate,7thus producing low plasma concentrations. Theseindividuals are usually symptomless, and some aredetected by routine estimation of plasma urate bymultichannel analysers. PZA administration does notreduce the urate excretion in these individuals, andthere are probably three different types of lesiondistinguished, one affecting reabsorption throughoutthe whole nephron, the others only affecting pre- orpostsecretory reabsorption.

Defects in urate reabsorption also occur in patientswith generalised disease of the proximal tubule (theFanconi syndrome) in whom abnormal urinarylosses of glucose, amino acids, bicarbonate orphosphate may occur as a result of inherited oracquired tubular lesions-for example, cystinosis,Wilson's disease, galactosaemia.8 In such conditionsattention is usually directed to those aspects of thesyndrome which cause symptoms such as theacidosis or rickets arising from bicarbonate orphosphate wasting respectively, but these patientsalso have a very high clearance of urate and a verylow plasma urate concentration.

Rather few studies of these lesions have beenmade, but PZA supresses the urinary excretion ofurate, with the inference that the defect is principallyone in postsecretory reabsorption.

RENAL FAILUREThe major problem in renal disease, however, is therenal handling of urate in patients with mild orsevere uraemia. Obviously, humans and otherprimates are at risk of joining birds, snakes andother reptiles in developing widespread fatal de-position of uric acid crystals during uraemia.Fortunately, this does not happen and even clinicalgout apparently secondary to chronic renal failureis very rare, being noted in only 17 of 1600 patientswith uraemia in one series.9

In uraemia, although the plasma concentrationsof urea and creatinine may increase thirty to forty-fold, that of urate does not. Up to about twice thenormal plasma concentration of creatinine (-thatis, down to about half the normal glomerularfiltration rate) the plasma concentration of uric acidrises approximately in parallel (Fig. 5) At this pointthe rise in the concentration of urate in the plasmaflattens off despite a further fall in the glomerularfiltration rate, so that the concentration of urate in

081

E 06

C

E 0-6EIVa

02

' -*" .' ~ ...

16,, i. .

100 300 500 700 900Plasma creatinine (Aumol/l)

1100

Fig. 5 The relation between plasma creatinine andplasma urate at various degrees of renal failure.

the plasma is still, on average, only about twicenormal even in individuals with terminal uraemia.10As renal failure progresses the urinary excretion

of urate falls steadily, but much more slowly thanwould be predicted from the fall in the glomerularfiltration rate, so that in terminal uraemia it is onlyone-half or one-third normal." Evidently the nettubular reabsorption of urate must fall from thenormal value of about 90% in health, to as little as20% in terminal uraemia. Correspondingly, theexcreted fraction increases from 10% to as much as80% of that filtered.12 How this adaptation occursis not clear, and is unlikely to be settled until there ismore accurate information on the tubular handlingof urate in health. Some compounds retained inuraemia are uricosuric for example, hippurates,and these may be the factors responsible for thisaspect of adaptation to the uraemic state.Even so, the reduction in total excretion of urate

suggests either that urate production is reduced orthat some extrarenal excretion increases as renalfunction declines. Although there has been somecontroversy, and data are not extensive, the con-sensus from studies using '4C-urate is that urateproduction in uraemia is normal. Also, it is knownthat in health some urate, probably one-third, butperhaps as little as one-tenth of the total production,is excreted into the gut and degraded there byuricase-bearing bacteria. This almost certainlyincreases in uraemia, although direct information onthis point is limited to the study of two patients.

ROLE OF THE KIDNEY IN THE GENESIS OF

GOUTOne hundred and thirty-two years ago, Garrodspeculated that the cause of gout might be "a loss ofpower ... in the uric acid excretory function of thekidney." Before we can examine the suggestion thatgout-or at least some gouty patients-suffer froma disorder of urate excretion, we must examine

3 *

IJ

1 249

copyright. on M

arch 12, 2020 by guest. Protected by

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.34.11.1245 on 1 N

ovember 1981. D

ownloaded from

C0ameron, Simmonds

briefly the origins of uric acid. The body pool ofurate, and hence the plasma urate concentration, isthe result of a balance between production, ingestion,and excretion (Fig. 6). Ingested nucleotides andpurines are largely degraded by gut and liverenzymes, whilst endogenous purine synthesis matchesthat incorporated into tissue nucleotides RNA andDNA. The synthesis of each molecule of purinereq uires the consumption of six molecules of ATP,but the bulk of the purine bases released fromnucleotide degradation are "salvaged" for newnucleotide synthesis by the expenditure of a singlemolecule of ATP, principally through the agency ofthe enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT, EC 2.4.2.813). The free nucleo-tides are powerful inhibitors of de novo purinesynthesis, and thus this enzyme functions as part ofan inhibitory pathway limiting and regulatingpurine synthesis, restricting the availability ofpyrophosphate-ribose phosphate (PP-ribose-P) inthe process.

Production -

ingestion

Tophi

GutI Excretion

Misci bleurote o Urinarypool excretion

I

Plasmaurate

Fig. 6 Factors imiportant in the production anid

disposal of iarate in the body.

The possible causes of increased plasma urateconcentration are (i) overproduction of endogenouspurine, (ii) increased intake of exogenous dietarypurine, (iii) decreased excretion of purine.

Purine production can be measured using theincorporation of radiolabelled precursors, but suchmethods are not suitable for use in routine clinics.A simpler way of assessing the de novo productionof purines is to place the patient on a purine-freediet for five to seven days and measure the urinaryexcretion of urate, since by this time purine excretionwill equal endogenous production. In this way lessthan 100% of patients with gout have been found toexcrete an abnormally large amount of urate ( >4mmol/day). In most of these the overproduction ismodest, but in a few individuals great quantities ofurate are produced-up to 5 or even 10 timesnormal. In some of these patients abnormalities ofpurine enzymes can be discerned, the best-known ofwhich is the Lesch-Nyhan syndrome due to theabsence or partial absence of the regulatory salvage

enzyme HGPRT.13 Most of the hemizygotes for thisdeficiency are mentally defective and exhibit atheto-sis and a remarkable, bizarre tendency to self-mutilation. Others (and all heterozygotes) are muchless affected, and may present as otherwise normalgouty overproducers of urate. Another enzyme,PP-ribose-P synthetase (EC 2.7.6.1.), may be presentin a mutant form which has increased activity, andwhich consequently accelerates purine synthesis.This condition, like the Lesch-Nyhan syndrome, isinherited as a sex-linked recessive trait since theDNA coding for the enzyme is carried on the Xchromosome.

Purine ingestion has been known for millenliato be high in subjects with gout, as the popularstereotype of the gouty subject shows. Gout is adisorder of affluent societies with diets rich inpurines; during times of hardship uric acid con-centrations fall and clinical gout almost vanishes.These observations, and the extensive data on theincrease in urinary purine and plasma urate con-centrations in normal and gouty subjects on in-creasing purine intake, show the importance ofdietary purine in precipitating clinical gout. Thenature of the ingested purine may be more importantthan is realised, as some forms of purine forexample, from RNA, are absorbed and catabolisedmore readily than others.

However, neither overproduction (tinless suddenand massive) nor overingestion are likely to raisethe concentration of urate in the plasma, if the renalresponse is normal. When normnal subjects have theirurate production reduced by the administrationi ofallopurinol, or raised by ingestion of yeast, which isrich in RNA, then the plasma urate rises little withincreased intake, the increase in the excretion ofurate being dramatic when the rise in plasma urateis modest (Fig. 7). When the same studies are under-taken on gouty subjects, an immediate difference isapparent (Fig. 7), some of which comes from theinclusion of normo- and hyperexcretors of tirate.The striking difference is that for any plasma urateconcentration, the gouty patients' excretion ofurate was consistently less than in the normalsLibjects. Looked at another way, these data demon-strate that to generate the same excretion of urate,the gouty patient must "run" a higher plasma urateconcentration.The nature of this defect is not yet clear, since so

many early studies must be re-evaluated in the lightof recent knowledge of how complex the renaltubular handling of urate is. However, some recentevidence from studies using PZA or benzbromaronesuggests that gouty patients underexcrete uratebecause of a defect in tubular secretion.4

These findings suggest that, in the majority of

1 250

copyright. on M

arch 12, 2020 by guest. Protected by

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.34.11.1245 on 1 N

ovember 1981. D

ownloaded from

Uric acid, gout and thekidney2

57

E3

E

2 2

1

Normal Gout

I

/

I

d2 0 4 0 6 08Plosma urate (mmol/l)

10

Fig. 7 The relation between plasma urate concentrationand urate excretion in normal individuals and goutysubjects, when plasma urate varies spontaneously or inresponse to treatment (modified from Wyngaarden andKelley, 1972).25

gouty patients, a combination of events is needed toproduce hyperuricaemia and the clinical syndromeof gout. These are overproduction of urate, usuallymodest and probably genetically determined, or a

large intake of readily-absorbed purines, togetherwith a defect of the kidney which cannot respond toa purine load without an abnormal rise in plasmaurate concentration. Thus, renal hypoexcretion ofuric acid can be considered one of the major riskfactors determining the appearance of clinical gout.

This raises the unsolved question of why clinicalgout is not commoner than it is in patients withraised plasma urate as a result of renal failure. Twopossible explanations have been advanced, neitherof which is convincing. One suggests that urate ismore soluble in uraemic than in normal plasma, theother that the inflammatory response normallyevoked by urate crystal deposition is muted by theimmunosuppression associated with uraemia.The kidney also seems to be the site of the dif-

ference between men and women in their liability togout. The female kidney excretes a higher pro-

portion (10-12%) of filtered urate than the malekidney (8-10 %), which gives males their higherplasma urate and makes them more vulnerable tooverproduction or overingestion.3 This difference isnot seen in postmenopausal women who thusbecome more liable to gout.

GOUTY NEPHROPATHY AND ACUTEHYPERURICAEMIC RENAL FAILURE14Urinary abnormalities such as mild proteinuria andabnormalities of urinary sediment are commnon in

gouty patients, but although renal failure wascommon and one of the principal causes of deathfrom gout until 20-30 yr ago, it is now rare.'5 16 Thecause of renal faiiure in gout has been much debated.Some suggest that all the renal damage follows theassociated vascular disease of gout,15 while otherssee a central role for the deposition of uric acid orurate crystals within the kidney, which is the onlyfeature specifically associated with gout.14The reasons for the decline in the mortality from

renal failure in gout are now impossible to deter-mine, but it is tempting to relate them to the de-creasing frequency of the disease associated withmoderation of purine intake and with the moreeffective treatment of the disease, first with uri-cosuric agents and then with allopurinol. Today,gross deforming tophaceous gout is a rarity, andassociated hypertension will normally receiveeffective treatment.The nature of "gouty nephropathy"-or even its

existence as such-has been the subject of muchdebate. On the clinical side there is no doubt thatsome patients with classical gout-men of middleage with a high purine intake in the form of food orbeer suffer a gradual decline in renal functionwhich can be arrested by control of their plasmaurate concentrations using allopurinol. However, anumber of such patients are also hypertensive, andin many it is difficult to assess the relative importanceof treating hyperuricaemia and hypertension.Equally, it is clear that this type of patient is nowless common, and the decline in numbers of thisformerly common group has brought another groupof gouty patients with renal failure into prominence.These are young patients aged between 20-40 yrwith precocious onset of gout in childhood, or earlyadult life, in whom renal failure is an early feature,men and women being affected equally. A familyhistory of gout is common in this group, and in someof these families hypertension is absent initially, soit seems clear that this cannot be the feature causingthe renal failure. Renal biopsies show an interstitialnephropathy with tubular atrophy and glomerulo-sclerosis, but urate crystals are rare.'7

Experimentally, it has been shown that crystalnephropathies due to various purines, includingxanthine and uric acid, can cause interstitial scarringas a long-term result.18 At this point the question ofsodium urate and uric acid must be raised. In theinterstitium of the kidney the ambient pH is that ofplasma, and the predominant species of purine is theneedle-shaped sodium urate. Within the tubules,however, the pH may be 5 0 or less and the pre-dominant species will be amorphous uric acid,and there is no doubt that the predominant lesion inpatients with acute overproduction of urate due to

1251

copyright. on M

arch 12, 2020 by guest. Protected by

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.34.11.1245 on 1 N

ovember 1981. D

ownloaded from

Cameron, Simmonds

treatment with cytotoxic drugs (discussed below) isintratubular deposition of uric acid. The origin ofthe interstitial amorphous sodium urate in chronicgout nephropathy is controversial. Some see it as theresult of the ambient plasma urate concentration,others (including ourselves) as the result of erosionof uric acid crystals out of the tubules with sub-sequent transformation to sodium urate. Bothmechanisms may be operative; in any case, both uricacid and sodium urate are capable of generatinginflammation with secondary scarring.

This argument is not merely academic, because ifthe primary abnormality is the deposition of sodiumurate interstitially, appropriate treatment is to lowerthe plasma urate concentration and the method ofachieving this is unimportant. If, on the other hand,the initial event is the intratubular deposition ofuric acid crystals, then the tubular concentration ofuric acid will be seen as the crucial event, and uri-cosuric agents will be contraindicated. It seems besttherefore in patients with gout and renal impairmentto reduce urate production with allopurinol, whichshould be effective in either case. It must be re-membered, however, that its active metabolite,oxipurinol, even in patients with normal kidneyfunction, has a long half-life since, unlike its parentdrug, it is reabsorbed in the tubules; and the dose ofallopurinol may have to be reduced to as little as100 mg daily or even 100 mg three times weekly inadvanced renal failure, to minimise the risk of bonemarrow depression.

In some patients, even control of both hyper-tension and plasma urate concentration fails toarrest a decline in renal function, and this againraises the question of exactly what determines theappearance, severity and progression of interstitialnephropathy in gouty patients. It seems likely thatthere are several groups which can be identifiedrather tentatively, some of which respond to availabletreatment. Even so, the central fact is that, today,chronic renal failure is rare in gout. Gout is theprimary cause of renal failure in less than 1% ofpatients treated by regular dialysis or transplanta-tiort in Europe as a whole, or even in our own unitwhich has a particular interest in gouty nephro-pathy.'9

Fortunately, the acute hyperuricaemic renalfailure20 which occurs most commonly when there ismassive overproduction of purines as a result oftissue breakdown, also is becoming rare. Thecommonest circumstance is the treatment ofleukaemia, lymphoma or myeloma, but rare in-stances after spontaneous remission or the treatmentof solid tumours have been recorded. The appear-ance of renal failure can be averted in almost allcases by ensuring a high volume of alkaline urine by

means of a high fluid intake coupled with a diureticand sodium bicarbonate, and above all, by givingallopurinol to distribute the purine load over thethree purines hypoxanthine, xanthine and uric acid,through its action in blocking xanthine oxidase.Whilst hypoxanthine is very soluble, xanthine is asinsoluble as uric acid in neutral and acid urine but itssolubility does not increase in alkaline urine. A fewcases of xanthine stones or xanthine nephropathyhave been reported in patients treated for malig-nancies with allopurinol, and also occasionally inother patients with gross overproduction of urate,such as the Lesch-Nyhan syndrome, treated similarly.

URIC ACID STONESUrate is least soluble in the form of uric acid in acidurines (Fig. 1). An interesting observation is thatmany patients with gout, but otherwise normal renalfunction, pass urine with a low pH in the range4 8-5 4 throughout the 24 hours of the day. Thiscontrasts with normal individuals, who, dependingon their diet, show a pH above 6 at some time in theday as part of diurnal variation. A persistently lowurine pH is also seen in some non-gouty uric acidstone-formers, and is associated with a defectivetubular secretion of ammonium, the mechanism ofwhich is obscure10 the often-quoted idea that thisresults from diversion of glutamate from ammoniumto urate production has been shown to be untenableon quantitative grounds. In young patients with gout,stone formation often precedes the onset of thearthritis.The importance of the acid urine in predisposing

to the formation of urate stones is clear, as Fig.shows. Obvious steps in treatment are: (i) to increaseurine volume, (ii) to increase the pH of the urine,(iii) to reduce urinary urate excretion by allopurinol.In practice, the first two alone usually suffice2l but itis important to realise that sodium itself, given assodium bicarbonate, actually decreases the solu-bility of urate in the urine, by a common ion effect.It is important, therefore, to ensure that the urinevolume is greatly increased, since the solubility ofurate in the urine increases as the square of thevolume, again because of interaction with other ions.An interesting observation is that gouty patients

also have an increased tendency to form oxalatestones. This may be related to competition by excessuric acid for inhibitors of crystallisation in the urine,or to the action of uric acid crystals as nuclei for thecrystallisation of the calcium oxalate; but an effectof purine metabolism on oxalate production is alsopossible. In passing we can note that in addition touric acid and xanthine, an even more insolublepurine, namely 2,8 dihydroxyadenine, (2,8-DHA),the 6-amino analogue of uric acid, may on rare

1252

copyright. on M

arch 12, 2020 by guest. Protected by

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.34.11.1245 on 1 N

ovember 1981. D

ownloaded from

Uric acid, gout and the kidneys

occasions form radiolucent stones which are easilyconfused with uric acid chemically, although theappearance is distinctive;22 stones of 2,8-DHA areblue grey and crumbly, in contrast to the hard,yellowish urate stones. 2,8-DHA is excreted inindividuals who are homozygotes for the deficiencyof adenine phosphoribosyltransferase (APRT, EC2.4.2.7), the companion purine salvage enzyme toHGPRT. This deficiency makes adenine available foroxidation by xanthine oxidase to 2,8-DHA, so thatallopurinol should be effective treatment. UnlikeHGPRT, APRT is not apparently important in theregulation of de novo purine synthesis, so thesepatients do not have gout. They may, however,present in renal failure, either because of urinarytract obstruction by the stones, or because of adiffuse interstitial nephritis associated with 2,8-DHAcrystals in the tubules and interstitium. The latterobservation supports the idea that intratubular urateis important in producing the interstitial nephritisof gout.

SYMPTOMLESS HYPERURICAEMIASince we now have, in allopurinol, a powerful toolfor the reduction of plasma urate, it has beenquestioned whether allopurinol should be used whena raised plasma urate concentration occurs withoutapparent harmful effects. The first such condition issymptomless hyperuricaemia usually, but not always,found in association with mild hypertension. Treat-ment of the latter with thiazide diuretics, of course,may further increase the plasma urate and mayprecipitate acute gout. A raised plasma urate con-centration has been identified as a risk factor forvascular disease.6 A study of hypertensives withsymptomless hyperuricaemia for up to four yearsfailed to show any difference in creatinine clearance,23but this does not exclude a longer term effect. Ifthe plasma urate persistently exceeds 0-60 mmol/lthe likelihood of an attack of clinical gout is veryhigh, and prophylactic treatment is justified. Atpresent no secure advice can be given for those witha plasma urate in the range 045-0 60 mmol/l,except that dietary purines should be restricted.The second such condition is uraemia from causes

other than gouty nephropathy. In fatal cases uratecrystals have been demonstrated in the renalmedulla in alcohol-fixed material, and this has ledto the suggestion that the decline in renal functionmight be accelerated by the raised plasma urate.24The likelihood of this depends on whether the inter-stitial urate plays an important part in the patho-genesis of gouty nephropathy, and whether itoriginates from ambient plasma urate or fromtubular uric acid crystals. Allopurinol has not beentried in non-gouty uraemics, and for the moment, in

1253

view of its side effects and the accumulation of itsmetabolite oxipurinol in renal failure, such treatmentseems too speculative to recommend.

TRANSPLANTATION AND LEUKAEMIAFinally, the dangers of combined treatment withallopurinol and purine analogues needs to bementioned. Both azathioprine and its metabolite,6-mercaptopurine are oxidised to thiouric acid byxanthine oxidase, and allopurinol prolongs theactions of the drugs indefinitely. Even moreinterestingly, in cyclophosphamide-treated patientsleucopenia is more frequent in patients also givenallopurinol.

References

Roch-Ramel F. Renal excretion of uric acid in mammals.Clin Nephrol 1979;12:1-6.

2Steele TH, Rieselbach RE. The renal handling of urate andother organic anions. In: Brenner BM, Rector FC, eds.The kidney Vol 2. Philadelphia: WB Saunders, 1976:442-67.

3Wolfson WQ, Hunt HD, Levine R, et al. The transportand excretion of uric acid in man. J Clin Endocrinol 1949;9:749-66.

4Levinson DJ, Sorensen LB. Renal handling of uric acid innormal and gouty subjects: evidence for a 4 com-ponent system. Ann Rheum Dis 1980;39:173-9.

5 Emmerson BT. Chronic lead nephropathy. Kidney Int1973 ;4:1-5.

6 Anonymous. Diuretics, hyperuricaemia and tienilic acid.Lancet 1980;ii:681-2.

7de Vries A, Sperling 0. Inborn hypouricemia due to iso-lated tubular defect. Biomedicine 1979;30:75-80.

8 Wilson DM, Goldstein NP. Renal urate excretion inpatients with Wilson's disease. Kidney Int 1973 ;4:331-6.

9 Richet G, Mignon F, Ardaillou R. Goutte secondaire desnephropathies chroniques. Presse Medicale 1965 ;73:633-8.

10 Hatfield PJ, Simmonds HA. Uric acid and the kidney:Current concepts. Guy's Hospital Reports 1974;123:271-97.

Emmerson BT, Row PG. An evaluation of the patho-genesis of the gouty kidney. KidneY Int 1975;8:65-71.

12 Danovitch GM, Weinberger J, Berlyne GM. Uric acid inadvanced renal failure. Clin Sci 1967;43:331-41.

13 Seegmiller JE. Human aberrations of purine metabolismand their significance for rheumatology. Ann RheumDis 1980;39:103-17.

'4 Cameron JS, Simmonds HA. Gout and crystal relatednephropathy. Contrib Nephrol 1979;16:147-53.

15 Berger L, Yu TF. Renal function in gout. IV. An analysisof 524 gouty subjects including long-term follow-upstudies. AmJMed 1975;59:605-13.

16 Gibson T, Simmonds HA, Potter CF, Jeyarajah N,Highton J. Gout and renal failure. Eur J Rheum Inflam1978;1 :79-85.

17 Simmonds HA, Warren DJ, Cameron JS, Potter CF,Farebrother DA. Familial gout and renal failure inyoung women. Clin Nephrol 1980;14:176-82.

18 Farebrother DA, Hatfield P, Simmonds HA, Cameron JS,Jones AS, Cadenhead A. Experimental crystal nephro-pathy. One year study in the pig. Clin Nephrol 1973;4 :243-50.

copyright. on M

arch 12, 2020 by guest. Protected by

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.34.11.1245 on 1 N

ovember 1981. D

ownloaded from

1254

Simmonds HA, Cameron JS, Potter CF, Warren D,Gibson T, Farebrother D. Renal failure in young

subjects with familial gout. In: Rapado A, Watts RWE,de Bruyn CHMM, eds. Purine metabolisnm in nian IllPart A. New York: Plenum Press, 1980:15-20.

20 Robinson RR, Yarger WE. Acute uric acid nephropathyin man. Arch Intern Med 1977;137:839-40.

21 de Vries A, Sperling 0. Recent data on uric acid lithiasis.Adv Nephrol 1974;3:89-1 16.

22 Simmonds HA. 2,8-dihydroxyadeninuria-or when is a

Lric acid stone not a uric acid stone? Clin Nephrol 1979;12:196-7.

2 Rosenfeld JB. Effect of long-term alloppurinol administra-tion in normotensive and hypertensive hyperuricemicsubjects. In: Sperling 0, de Vries A, Wlyngaarden JB,eds. Piurine metabolismti in nman. New, York: Plenum Press,1976:581.

Cameron, Simmotnds24 Verger D, Leroux-Robert C, Gauter P, Richet G. Les

tophus goutteux de la medullaire renale des uremiqueschroniques. Nephron 1967 ;4:356-70.

25 Wyngaarden JB, Kelley WN. In: Stanbury JB, Wyni-gaarden JB, Fredrickson DS, eds. Metabolic basis olinherited disea.se 3rd ed. New York: McGraw-Hill, 1972:889.

NB A detailed account of all aspects of gout and the kidneyis to be found in Wyngaarden JB, Kelley WN. Gouit andhypriuricenmia. New York: Grune & Stratton, 1976.

Requests for reprints to: Prof JS Cameron,Clinical Science Laboratories, 17th Floor Guy's Tower,Guy's Hospital, London SEI 9RT, England.

copyright. on M

arch 12, 2020 by guest. Protected by

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.34.11.1245 on 1 N

ovember 1981. D

ownloaded from