Guidelines for the Management of Hyperuricemia and Gout

Guidelines for the Management ofHyperuricemiaand Gout
Abridged Edition
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Committee for the Preparation of Guidelines for the Management ofHyperuricemia and GoutJapanese Society of Gout and Nucleic Acid Metabolism

Chapter I.
l.

Introduction

Current status of gout and hyperuricemia in Japan
Gout was a rare di sease in Japan prior to 1960. However, with the Westernizationof the Japanese diet and increased alcohol consumption, the incidence of gout has been
increasing every year. At present, the estimated number of patients with gout is 300,000
to 600,000 and the incidence continues to increase. Hyperuricemi a, which is the disease
underlying gout, also is on the increase. Furthermore, this disease was formerly seen inpatients from their ages of 50s and now has a trend to shift their morbidity peaks
forward to younger patients with 30s of ages.
Although hyperuricemia has become a common lifestyle-re lated disease, there
have been no large-scale prospective studies in Japan to investigate whether untreatedhyperuricemia can lead to gouty arthritis, renal disorder, urolithiasis, or cardiovasculardisease. There are also no worldwide efforts to conduct intervention studies ofurate-lowering agents.
Treatment guidelines based on sufficient consensus on the treatment ofhyperuricemia and gout has not been available due to the lack of such studies. Thus, toaddress this current situation and to meet the needs of the clinician, the Japanese Societyof Gout and Nuc leic Acid Metabo lism has prepared the "Guidelines for theManagement of Hyperuricemia and Go ut" employing the evidence-based method asmuch as possible.
Th is publication is the abridged edition of the Guidelines.
In this publication, statements that are "h ighly recommended (based on sufficientevi dence)" are shown in bold red letters and those that are " recommended (based onconsensus)" are shown in bold blue letters for easy reference.

Chapter II.
l.

Definitions and Evaluations

Epidemiology of gout and hyperuricemia in Japan
Gout was previously considered a rare disease, but the number of patients

increased dramatically during the era of rapid economic growth in the 1960s and 1970s,
and today it is considered to be a common illness. Based on the "Comprehensive Surveyof Living Cond itions of the People on Health and Welfare "conducted by the Ministryof Health, Labour and Welfare, there were 590,000 pati ents w ith gout in 1998, which
was double the number in 1989. Accompanying this increase is the recent phenomenonof a rapid rise in the morbid ity of gout among people between 20-30 years of age .

2

For hyperuricemia, which underlies gout, the incidence rate has also
increased from about 5% of adult men in the 1960s to about 15% in the 1970s to
early 1980s and about 20% in the late 1980s to 1990s . For women , the incidence rate
is about I% in premenopausal women and 3-5% in postmenopausal women .
Symptoms of gout, as manifestations of the urate crystal deposition syndrome, areepitomized as arthritis (gouty attack), gouty tophus, and renal disorder including urinary
calculus. However, in addition, gout patients often concurrently have obesity,

hypertension, hy perlipidemia, glucose intolerance, etc., and the cumulative effectsof these complications are thought to affect the prognosis of gout patients. Insulin
resistance is also considered to be invo lved in the cumulative effects of complications.
Amo ng hyperuricemic patients, about 80% have some concurrent lifestyle-relateddisease .
It is known that high serum urate level is a risk factor for ischemic heart disease,and two large cohort studies conducted in Japan have shown that hyperuricemia is anindependent risk factor for cardiovascular and cerebrovascular disease.

Manyepidemiological studies have shown that hyperuricemia is an independent predictive
factor for cardiovascular and cerebrovascu lar events, but there has been controversy
over whether hyperuricemia is indeed a risk factor. It is therefore necessary to await theresults of further intervention studies in this area.

2.

Diagnosis of gout and definition of hyperuricemia

A.

Diagnosis of gout

(1) Clinical picture
The arthritis of gout is called a gouty attack and is often seen in the joints of thelower extremities, such as the first metatarsophalangeal joint. The patient experiences
pain, swelling, and redness, with difficulty in walking, but the symptoms improve in
7-10 days . The patient is then completely asymptomatic until the next attack. If thepatient is left untreated without adequate control of the serum urate level, repeatedepisodes of gouty arthritis lead to chronic arthritis. In addition, granulomatous tissue
with urate called gouty tophus may also develop.
Persistent hyperuricemia can also lead to interstitial nephritis in the renal medulla,
resulting in gout nephropathy appearing as a complication. Such progression to uremia
from that stage was formerly responsible for the majority of deaths in patients withgouty arthriti s, but uremia has greatly decreased due to systematic treatment ofhyperuricemia.

3Table 11.

Standards for the diagnosis of gouty arthritis

The presence of characteristic urate crystals in the joint fluid

2. A tophus proved to contain urate crystals by chemical means or polarized lightmicroscopy
3. The presence of 6 of the following 11 clinical , laboratory, and x-ray phenomena
listed below:a) More than one attack of acute arthritisb) Maximum inflammation developed within 1 dayc) Attack of monoarticular arthritisd) Joint redness observede) First metatarsophalangeal joint painful or swollenf) Unilateral attack involving first metatarsophalangeal jointg) Unilateral attack involving tarsal jointh) Suspected tophusi) Hyperuricemiaj) Asymmetric swelling within a joint (roentogenogram)k) Complete remission of arthritis

Table 2

Important reminders in the diagnosis of gouty arthritis

1. Serum urate level during a gouty attack may be low and thus is of low diagnostic
value.
2. Upon obtaining joint fluid, submit it immediately for microscopic examination andidentify whether urate crystals are present.
3. Gouty tophus has diagnostic value but is uncommon .

Table 3

Classification of hyperuricemia by urinary urate excretion(EuA) andurate clearance (CuA)
Disease type

EuA (mg/kg/hr)

Over-producer typeof urate
Under-excretor typeof urate
Mixed typeC uA (mL/min)> 0.51

and~ 6.2< 0.48or< 6.2> 0.51and< 6.2(2) Diagnosis
Gout is a crystal-induced arthritis caused by urate that has deposited into the joint
space

4

from

persistent

hyperuricemia,

and

is

thereforeclearly

distinctfromhyperuricemia. The diagnosis of gouty arthritis is made when acute arthritis appears in apatient with hyperuricemia, in which acute arthriti s with redness and swelling often
develops in the first metatarsophalangeal joint or other joint in the foot.
The diagnostic standards based on the American College of Rheumatology areused in Japan(Table 1) . Whenever possible, it is recommended that the joint fluid froma patient with acute arthritis be examined by polarized light microscopy for the presenceofneedle-like monosodium urate crystals phagocytized by neutrophils to confirm thediagnosis (Table 2).

(3) Differential diagnosis
Since various rheumatic diseases cause acute arthriti s, it is necessary todifferentiate gout from such diseases as chronic rheumatoid arthritis , pseudogout, etc. lt
is often necessary to differentiate gout from other causes of pain or swelling developingin the lower extremities such as hallux valgus, paronychia, cellulitis, sprain, bursitis,
etc.

B.

Definition of hyperuricemia
Regardless of age or sex, a plasma uric acid solubility of 7.0 mg/dL is

considered to be the upper limit of the normal range, and patients with a value
exceeding this limit are defined to be hyperuricemia.

3.

Measurement of uric acid
Uric acid can be measured by various analytical methods such as the reduction

method based on the reducing abi lity of urate, the enzymatic method using the uricase,and high-performance liquid chromatography (HPLC).

ln Japan, the reduction method was the most popular method until the 1970s, thenthe use of enzymatic method increased from the 1980s. Currently, at most institutions,uric ac id is measured by the uricase peroxidase method using an auto analyzer.
Differences between institutions have improved, and this method is considered to bereliable.
The timing of the blood drawing may be flexible independently from meals, butestablishing the diagnosis of chronic hyperuricemia requires several repeatedmeasurements in consideration of the physiological variations in serum urate levels.

4.

Disease classification
Hyperuricemia can be classified into the overproduction type of urate5

(increased production of urate), the underexcretion~ · peof urate (decreased

urinary excretion of urate), and the mixed type inrnlYing a combination of both.
The disease classification can be definitively established by measuring theurinary excretion of urate (EL\) and urate clearance (CuA) under fasting, waterloading, and restriction from purine-rich diet as well as the creatinine clearance(Ccr) to correct for renal function. EuA > 0.51 mg/kg/hr means the overproduction type
ofurate, while CuA < 6.2 mL/min means the underexcretion type of urate (Table 3).
Chapter III.

1.

Treatment

Treatment objective and treatment strategy
The treatment objective of hyperuricemia and gout is primarily to prevent

onset of gouty arthritis. The a\'ailable data indicate that serum urate control to
4.6-6.6 mg/mL offers the lowest incidence. ln particular, it is important to preventthe onset or progression of complications such as renal disorder (gouty kidney)

and urolithiasis caused by urate precipitation.
Furthermore, hyperuricemia and gout are known to often complicate withlifestyle-related diseases such as hyperlipidemia, hypertension, glucose intolerance,and obesity, and it has been suggested that these complications for hyperuricemia leadto increased incidence of ischemic heart diseases and cerebrovascular disorders. Thus,
the physician must not only control the serum urate level but also take sufficientconsiderations for these complications.
Based on these considerations, it is desirable to maintain serum urate at aleYel of not more than 6 mg/dL.

Clinically, once the gouty arthritis has been treated and the clinical course is undercontrol, a urate-lowering agent is selected based on the disease type and complications.
The urate-lowering agent is started at a low dose, and the dose is gradually escalated
over the course of 3-6 months while monitoring the serum urate level and urinary urate
excretion to determine the appropriate maintenance dose. If a gouty arthritis recurs
during this period, the dose of the urate-lowering agent is kept constant until the arthritis
regresses .
At the same time, additional measures should be taken such as lifestyle guidance,
dietary therapy, and urologic management, for the treatment of lifestyle-related diseases
and any complications such as renal disorder and urolithiasis (Figure 1).

6Treatment of ac ute go uty
anhritis

Treatment during intermittent period (treatment
ofhyperuricemia)

II

Acute gou1
Dnigs for gouty

attackUrat e~ l owering

agent
Serum urate level

7 mg/dL
Gouty tophus

Diagnosis

Check for complications.
Determine maintenance dose of
Se lect urate-lowering age nt.
Patient education andurate-lowerin g age nt.
dietary guidance- - - - - - - - - - - - - - - -Urologicalmanagement

Treatment fo r
co mplicati ons

Figure 12.

Treatment strategy for a patient with gouty arthritis

Treatment of gouty arthritis
Gouty arthritis is generally characterized by intense pain , and while short lived,

extremely reduces the quality of life (QOL) of the patient. Thus, the aim of acutetreatment is to elim inate pain and improve QOL. In addition, because the patient's own
ex peri ence of the gouty arthriti s is important in introducing long-term management of
the underlying hyperuricemi a, the treatment cannot be considered completed once thepain of arthri tis has subsided.
Three th erapeuti c options avai lab le are colchicine, nonsteroida l anti-inflammatory
drugs (NSAIDs), and steroids. A ll have been demonstrated to have clinical efficacy.
One genera l approach is to g ive one tablet of co lchi cine at the aura phase of the gouty
flare and then g ive high doses of

SAIDs during the advanced stage for a short period

to subside the inflammation . Steroids are also effective an d have adva ntages in which
they ca n be selected by various administration routes such as --ora l, intramuscu lar, or
direct injection into the joint- to meet the needs of the pati ent conditi ons.

A. Colchicine
Administration in the aura phase of gouty attacks
In contrast to the U .S. a nd Europe, the genera l a pproach in Japan is to use sma ll

7doses of colchicine in the aura phase of gouty attacks. The administration of one
tablet of colchicine (0.5 mg) during the aura phase of gouty attacks can abort theattacks. For thi s reason, patients are prescribed co lchicine and instructed to have it with

them.
Colchicine shows insufficient efficacy when started at the advanced stage of theattack, even when given at high doses. At high doses, patients may experience adverse
reactions such as abdom in al pain or diarrhea, and followed by others such as vom iting
and muscle spasms.
Careful attention is also needed for the concomitant use of colchicine, withcimetidine, erythromycin, and nifedipine, since it may cause drug-interactions.
Table 4

List of NSAIDs indicated for gouty arthritis

Indication

Generic nameBrand nameDrug formulations

Dosage andadministration forgouty attack

Inflammatory
diseases
includinggouty attack

indomethacinlndacin, etc.

25 mg, 3 7.5 mg and 50
mg tablets,
slow-release capsules,
suppositories
100 mg tablets,
300 mg capsules

25 mg per dose, 1-3

naproxentimes a day

Initial dose of 400600 mg on the firstday, then 200 mg per
dose 3 times a day; or
300 mg every 3 hours
up to 3 times a day.
I00 mg and 200 mg Initial dose of 600apanol
fen bu fen
tablets
1,000 mg on the firstday, and be fo ll owed
200 mg per dose 3
times a day
pranoprofen
75 mg tablets
Initi ally 150 - 225 mg
Niflanper dose 3 times on
the first day, and be
fo llowed 75 mg per
dose 3 times a day
Norma lly 400 mg per
200 mg tablets
oxaprozin
Alvoday, to a maximumof 600 mg
Aspirin at low doses increases serum urate level and decreases at high doses.
Because aspirin at ana lgesic doses decreases urate level and may worsen or prolong the attack, it
hould not be used to during gouty attacks. Similarly aspirin derivatives and diflunisal shou ld not be
used during attacks.

8

NaixanNSAIDs

B.

'-SAIDs are the mainsta) for the treatment of acute inflammation of gout)
arthritis. In the ad\ anced stage of the gouty attack, a general rule is to administer
relathel~ghe higher doses for a short period of time (pulse 'iS.\IDs treatment).

For naproxen, 300 mg is given every 3 hours in 3 doses only for a single treatment.
Often thi s is sufficient to improve the symptoms. If the S) mptoms impro\"C, naproxen

is discontinued.
Jn the case that the residual arthritic pain continues to affect the activities of daily
life after the intense pain has improved, the conventional dose of NSA IDs may becontinued. \\i hen the s~mptoms impron•, it is then discontinued.
In Japan, there are only a few NSAIDs approved for National Health Insurance
reimbursement for gouty attacks (Table 4). The doses for attacks are generally higher
than those used for chronic rheumatoid arthritis.
Common problems in adm ini stration include induction or exacerbation of lesions
111

the gastric mucosa (especia lly gastric ulcer), exacerbation of renal disorder, andinteraction with warfarin, so the patient should be carefull) monitored for thesead' erse reactions. In patients with renal disorder or edema , it is preferable to use
NSAIDs with lower renal toxicity or to use steroids rather than NSAIDs. For patients on
warfarin treatment, stero id s rather than NSAIDs should be used.

C.

Steroids
In those cases that NSAIDs cannot be used, their administration is ineffective,or there observed multiple arthritis, oral steroids should be used. For example,
15-30 mg of prednisolone is to be administered to control the arthritis, with the dosebeing tapered by l /3 every week and stopped after 3 weeks. In severe cases, a low dose(about 5 mg/day) may need to be maintained for several months .
In arthritis patients with edema in the knee or elbow joint, ste rile puncture is madeinto the joint space and , after removing as much of the joint fluid as possible, steroids
can be injected into the joint. The joint fluid must be examined for the presence of
sodium urate crystals. If there is any suspicion of suppurati ve arthritis, the joint fluid
shou ld be tested for bacterial cu lture. In such cases, the steroid should not be injected
into the joint.

Note• During the gouty attack period, the patient should be instructed to take rest and cool
the affected joint and to avoid alco hol intake. In principle, changes in the serum urate

9level at the time of attacks can often exacerbate the attack, so a urate-lowering agent
should not be started during the attacks. However, if the patient is already on aurate-lowering agent, the patient should continue at the same dose of the agent with theaddition of colchicine, NSAIDs, or steroids.

3. Treatment of hyperuricemia
A.

Treatment objectives
For the hyperuricemic patient, the narrowly defined treatment objectives are toeliminate the deposition of urate deposits into tissues caused by the persistence ofhyperuricemia and to avoid gouty mthritis and renal disorder. In addition, it is also

important to note that the ultimate goal is to improve the long-term prognosis of
hyperuricemia and gout by taking into considerations to the complications such as
obesity, hypertension, and glucose and lipid metabolism abnormalities, with theconcomitant need for improvement in lifestyle. Undesirable lifestyles, such as
excessive intake and preference for purine-rich, lipid-rich, or protein-rich diet; drinking
habit; and lack of exercise, are not only a cause of hyperuricemia but also deeply related
to obesity, hypertension , and glucose and lipid metabolism abnormalities, etc. Thus, it isof primary importance to provide guidance for improving these aspects of the patient's
lifestyle.

Patients who have recurrent episodes of gouty arthritis or patients with gouty
tophus should be subjected to medical treatment (with urate-lowering agents)
regardless of the serum urate level. Patients who have a history or presence of urinary
calculus should be treated with allopurinol to reduce urate excretion into urine as we ll
as to control serum urate.

The optimum serum urate level to be achieved by treatment has not been
established yet in large-scale prospective studies. The current recommendation is
to maintain the urate level at not more than 6.0mg/dL that is a level below thetheoretical solubility for uric acid in human serum , as recommended by the JapaneseSociety for Purine and Pyrimidine Metabolism (now the Japanese Society of Gout andNuc leic Acid Metabolism).
Patients with asymptomatic hyperuricernia without gouty arthritis should beconsidered for the subjects for medication if the serum urate level is 8 mg/dL or greater,
but in case that the patient has no complications such as obesity, hypertension, or
g lucose or lipid metabolism abnon11alities, then the criteria for introducing the
medication may be app li ed flexibly (Figure 2).

10Hyperuricemia, serum urate> 7 mg/dL
Gouty anack or gouty tophus

Yes <II

No

Serum urate <: 8 mg/dL
Complications

Yes

Li festyle guidance

Medication

Medication

No
Serum urate

Serum urate< 9 mg/dL<: 9 mg/dL

Lifestyle guidance

Medication* uch as renal disorder, uri nary ca lcu lus, hypert ension, hyperl ipidemia, isch emic
heart disease , glu cose into lerance

Figure 2

B.

Algorithms for the treatment of hyperuricemia

Types of urate-lowering drugs and their adverse reaction s
Urate-lowering d rugs are class ifi ed to two categori es based on their mechani sm ofacti on, w hich pro mote urate excreti o n or those that inhibit uric acid prod uction. ln Japan,
there a re three drugs on the market that promote urate excreti on (uri cos uric) .
A llopurinol is the onl y availabl e inhibitor of uric ac id production (Table 5).
(1)

Uricosuric dru gs
Uricos uri c drugs enhance the urina ry excretio n of urate by inh ibiting the re nal

reabsorpti on of urate at rena l tubul es, resulting in decreased serum urate leve ls. At thesta rt of drug admi nistratio n, tho ug h the pati ent may show a trans ient in crease in urinary
excreti on of urate, after that o nce the poo l of urate in the body has norma li zed, theurinary exc reti on does not increase except the case o n excessive puri ne loading. It is

important to take careful attentions to the formation of urinary calculus in thetreatment.
(a) Proben ecid
Pro beneci d enab led a treatment fo r basic remedy of gout in the former period oftime when onl y symptomatic treatment could be appl ied and has been used sin ce 1951
as a maj o r drug fo r gout treatment.
In additi on to the effect on urate leve l, it also affects on the pharmacokinetics ofother drugs.

It inhi bits

the re nal excretion of sul ti npyrazone, salicyli c ac id ,11

indomethacin , penicillin, etc., and also inhibits hepatic uptake and reduces biliary
excretion of rifampicin and methotrexate. Low-dose salicylic acid reduces the uricosuric
effect of probenecid.
Incidenceof adverse

reactionislow, andinmost patientslong-term

administration is possible.

(b) B ucolome
This drug, initially developed as an

SAID in Japan, has a uricosuric action .

Concomitant use with low-dose aspirin decreases the blood concentration of bucolome
and reduces the uricosuric effect. Gastrointestinal disorders, headache and dizziness areseen as infrequent adverse reactions.

(c) Benzbromarone
Among the uricosuric drugs available at present, this drug has the most potent
uricosuric action. The uricosuric effect is achieved by inhibiting the post-secretory
reabsorption of urate in the renal tubules .

It does not interact much with other drugs and the reduction of its uricosuric effectby concomitant use with salicylic acid is small. lt may cause severe hepatic disorder inpatients with idiosyncrasy, but the incidence of adverse reactions is low, and currently
this drug is the most frequently used uricosuric agent in Japan .

12Table 5

Types, doses, and adverse reactions of urate-lowerin g drugs

Uricosuric
agentsUric acidproduction
inhibitor

Table 6

Generic nameBrand name(s)Daily dose andadministration

Adverse reactions

probenecid

Benecid500-2,000 mg in
2-4 divided
doses

Gastrointestinal disorder,
nephrotic syndrome,aplastic anemia, rash,
urinary ca lculus

bucolome

Paramidin

300-900 mg in
1-3 divided
doses

Gastrointestina l disorder,
rash, leukopenia, urinary
calculus

benzbromarone

Urinom1
arcaricin
Benzmarone
others25- 100 mg in
1-2 divided
doses

Fu lminant hepatitis,
gastrointestinal disorder,
urinary calcu lus

al lopurinol

Zy loric
Alosito l
Salobelothers

I 00-300 mg in
1-3 divided
doses

Toxic syndrome(hypersensitivity angiitis),
Stevens-Johnson
syndrome,
exfoliative dermatitis,
rash, ap lastic anemia,
hepatic dysfunction

Selection of urate-lowering drug

Indication of uricosuric agent

Indication of uric acid production inhibitor(a llopurinol)

•
•

•
•
•
•

Under-excretor type of urate
The case suffered from adverse
reactions by allopurinol

Over-producer type of urate
History or presence of urinary calcu lus
Moderate or severe renal dysfunction
The case suffered from adverse reactions
by uricosuric agents(2) Uric acid production inhibitor
The only drug ava ilable that inhibits the unc acid production is allopurino l.
Allopurino l inhibits xanthine oxidase, which involves in the final steps of purine
metabolism . lt was first introduced in 1964 for the treatment of gout and is wide ly used
today. Allopurinol lowers the serum urate level and also reduces the urinary excretionof urate. The oxidative metabolite of a ll opurinol, oxypurinol, has a strong inhibitory
action on xanthine oxidase and has a long half- li fe in the blood in the range of 18-30 hr,
so allop urino l has a relatively long-l asting inhib iting effect on uric acid production.
Conventional dosing in renal failure patients can result in the accumulation ofoxypurino l in the body, and may cause letha l toxic syndrome. Thus, it isrecommended that the dosage is adjusted based on the degree of renal d~· sfunction.

13

As an inhibitor of xanthi ne oxidase, it increases the blood concentrations of
6-mercaptopurine(6-MP) ,azathioprine,andtheophy lline;

affects

hapatic

drug-metabolizing enzymes; and prolongs the physiological half-life of antipyrine,probenecid, and warfarin. In addition , although the mechanism is unknown, it increases
the incidence of amp icillin-induced rash and has various other drug-drug interactions.
Note• It is recommended that urate-lowering drugs is started at the minimal dose to avoid theinduction of gouty a1thritis.
C

Selection of urate-lowering drug
A general rule is to use a uricosuric drug in patients with under-excretor typeof urate and to use a uric acid production inhibition (allopurinol) in patients withover-producer type of urate (Table 6). Tn the use of uricosuric drug, concomitant useof an agent for urine alkalization shou ld be recommended to prevent urinary calcu lus.
In the cases of renal disorder with a moderate degree or more (creatinine
clearance of 30 mL/min or less. or serum creatinine of 2 mg/dL or greater) or ahistor~of urinar~ calculus, allopurinol should he used.

In patients with renal

fa ilure, it is recommended the careful administration of allopurinol.

If adverse reactions prevent the use of a urate-lowering drug, the optional use ofanother drug is permitted even though it is out of the general rule. However, whenusing a drug incompatible with the disease type, the physician should particularly
take careful attentions to adverse reactions and start at as low a dose as possible,
and periodical hematology tests and urinalysis should be needed.

D.

Treatment of hyperuricemia without gouty arthritis or gouty tophu s (so-called

asymptomatic hyperuricemia)
Hyperuricemia (serum urate level of 7.0 mg/dL or more) without c linicalmanifestations such as gouty arthritis or gouty tophus is called asymptomatic
hyperuricemia. At this stage, it is important to prevent the progression to rena l disorderand the onset of urinary calcu lus and gouty arthritis, and to improve the risks ofatherosc lerosis that may often associate with hyperuricemia.
Aggressive measures should be taken at this point to incorporate lifestyle
management that can reduce the serum urate level. Furthermore, any comp li cations
must be properly contro lled and treated , and urologic management is also important.

14

In hyperuricemia patients with serum urate levels of 9.0mg/dL or more
showed a significantly higher prognostic incidence of gouty arthritis and urinary
calculus compared to those with lower values.
Jn patients with a family history ofhyperuricemia or gout, or complications (renal
disorder, urinary calculus or a history thereof, hypertension, hyperlipidemia, ischemic
heart disease, diabetes and obesity), the urate lowering treatment should be considered
if the serum urate is 8.0 mg/dL or more. In addition to nonpharmacologic therapy,
introductionsof medication

shouldalso

beconsidered.

In

patients

without

complications, introduction of medication should be considered ifthe serum urate is 9.0
mg/dL or more .

Note• A rapid decrease in serum urate level can elicit gouty arthritis, urinary calculus, oradverse drug reactions, so it is preferable to reduce the urate levels gradua lly.
• The physician should li st all drugs for prescriptions and carefully consider potential
drug-drug interactions, with particular attention to those of cardiovascular drugs.

E.

Treatment during a gouty attack (arthritis) and during the intermittent period
In the treatment of hyperuricemia, it is important to reduce the serum urate level

without inducing acute arthritis, renal complications, or urinary calculus.
During a gouty attack (acute arthritis), changes in serum urate level will
deteriorate the attack, so urate-lowering drugs should not be started. Rather, remissionof the attack should be awaited through the administration of anti- inflammatory drugs.
About 2 weeks after the remission, the urate-lowering drug should be started at a low
dose ( 1/2-113 of the standard dose) and the dose should be gradually increased over a

period of 3-6 months to achieve the serum urate level of 6 mg/dL or lower.
If an episode of acute arthritis occurs in the patient taking the urate-loweringdrugs, the dosage of the drug should be maintained without change. At about 2 weeks
after remission , the dosage should be gradually increased again to achieve a serum urate
level of 6 mg/dL or lower.

Thereafter, the drug should be given at a maintenance dose to sustain aserum urate level of 6 mg/dL or lower.
Specifically, the patient is given a starting dose of allopurinol (at 50-100 mg/day),benzbromarone (25 mg/day), or probenecid (250 mg/day) once a day, and then given a
maintenance dose to achieve a serum urate level of 6 mg/dL or lower with allopurinol(at 100-300 mg/day, 1-3 times/day), benzbromarone (25-100 mg/day, 1-3 times/day), or15

probenecid (250-2,000 mg/day, 1-4 times/day).
When administering a uricosuric agent, the formation of urate calculus can beprevented by maintaining the urine pH at 6.0-7 .0 using a combination drug containing
potassium citrate and sodium citrate (a drug for urine alkalization, 3-6 g/day, 3-4
times/day) . Daily water intakes should be maintained with the daily urine volume of
2,000 mL or more.
Note• In order to find adverse reactions in the early stage, the patient should be periodicallymonitored by laboratory tests for hepatic function or peripheral blood . For
benzbromarone, the Safety Information of the Pharmaceutical and Food Safety Bureau,
Ministry of Health, Labour and Welfare mandates monthly laboratory tests for hepaticfunction for 6 months after the start of administration.
Tab le 7

Suggested a llopuri nol doses for renal functions

C0 , > 50 mL/min

I 00-300 mg/day

30 mL/min < Ccr::; 50 mL/min

100 mg/day

Ccr ::; 30 mL/min

50 mg/day

Hemodialysis

I 00 mg at end of dialysis session

Peritoneal dialysis

50 mg/dayF.

Use of urate-lowering drugs in patients with co mp lication of renal disorder
In many patients, hyperuricemia must be treated in the setting of renal disorder.

When renal function decreases, the effect of uricosuric drugs is blunted, so patients withrenal dysfunction are often treated with allopurinol , a drug that decreases the productionof uric acid.
However, it has been reported that allopurinol can cause serious adverse reactions
in patients with renal failure. For this reason , in patients with renal disorder, the doseof allopurinol should be adjusted for the degree of renal functions, as shown in
Table 7.
In patients with a moderate degree of renal failure with a creatinine clearance(Ccr) of 30 mL/min or greater, it is effective and safe to use concomitantly of small
doses of benzbromarone (25-50 mg/day) and allopurinol (50-100 mg/day).
Note• As to the serious adverse reactions on the renal dysfunctions , careful attentions should16

be taken for bone marrow suppress ion (pa ncytopeni a, ap lastic anemi a), dermal
hypersensiti vity reaction, and hepati c di sorder.

G.

Use of urate-lowering dru gs in patients with complications of hepatic

dysfun ction
ln patients w ith hepatic dysfunction, it is important to treat the complicatedhepatic di sorders to treat the hyperuricemia without exacerbating the hepatic
dysfunction .
Urate-lowering drugs can sometimes cause hepati c dysfunction as an adverse
reacti on, so carefu l admini stration is needed in patients with hepatic dysfunction. In
paiticular, benzbromarone is contraindicated in patients with hepatic dysfunction,and thus other urate-lowering drugs must be used.
When treating a patient with a urate-lowering drug, it is important to monitor
hepaticfunctionsperiodically.

In

ge neral ,urate-l oweringdrugs ,

exceptforbenzbromarone, can be started at a low dose and the dose gradually increased, to lower
th e serum urate to a stab le leve l. Benzbromarone requires month ly laboratory tests forhepati c function s fo r 6 months after the start of drug administration.

4.

Ma nage ment of patients with hype rurice mia or gout
Aside from the serum urate level , patients with hyperuri cemia or gout should bemanaged as follows .

A

Urologic management
Thi s Guideline differs from current clinical practices, m wh ic h urol ogic

management is not a part of the urate-lowering therapy but is considered to be an
independent component of the therapeutic programs.
Jn pati ents with hyperuricemi a or gout, concurrent urinary calcu lu s is common . It
is thought that acidic urine (pH less than 6.0) may be the reason . The urinary pH greatly
affects urate solubility. Maintaining urinary pH at the appropri ate level serves also toprevent the fo rmation of other urinary ca lcu lus induced by urate calcu lus and urate
crysta ll ization .
The first morning vo id of urine is tested to determine whether the urine pH is lessthan 6.0. Jf th e pH reading persistently confirms acidic urine, urine alka li zation isnecessary .
For this purpose, a combinati on drug with potassium citrate and sod ium citrate isoften used .

17

In patients with hyperuricemia, even if the serum urate level is 7.0-8.0 mg/dL
during the observation period, it is necessary to use urine alkalizing drug if the urine
pH is consistently less than 6.0. A persistent urine pH of less than 5.5 is an essential
indication for treatment in patients with urinary calculus or a history thereof.
When

using

uricosuric

drugs,aurinealkalizing

drugshouldbeusedconcomitantly.
B.

Lifestyle management

lt is important to address hyperuricemia as a lifestyle-related disease from theviewpoint of a cardiovascular risk factor. Management of the lifestyle has priority overurate-lowering therapy using drugs.
The increase in the incidence of obes ity following Westernization of the Japanesediet and the trend toward overeating have been the focus of attention as underlying
factors of lifestyle-related diseases, and this in turn emphas izes the importance of
dietary therapy, restriction of excessive alcohol consumption, and appropri ate exerc ise
therapy. The physician should counsel the patient to correct the aspects of li festy le thatcan be corrected and instruct the patient to prevent obesity. However, since suchli festy le guidance can be excess ive and decrease the patient 's quality of life, thephysician should undertake only practical aspects. Hyperuricemia that is not affected by
the patient' s li festy le shou ld be primarily subjected to urate-lowering therapy.

C.

General health maintenance
Patients with hyperuricemia often have other compl ication with li festy le-re lateddiseases, so the physician shou ld understand that the hyperuricemia is a part of multiple
risk factor syndromes along with such disea ses as obesity (v isceral fat obesity),
hyperlip idemia, glucose intolerance, and hypertension. It is currently unclear whether
measures to lower the urate level reduce the cardiovascular risk. The physician
should endeavor to reduce the serum urate level in the patient in the context ofgenerally improving the multiple risk factors by lifestyle management.
Fo r this reason , other li festyle-related diseases, especia lly complication withcardiovascular diseases, should be monitored periodically by ECG as well as tests forblood gl ucose and serum lipids. To monitor adverse drug reactions, tests for peripheral
blood, hepatic function, and renal function shou ld also be periodically performed.

18

C hapter I V.
1.

Treatm en t of C omplica tion s o r C oncu rrent Diseases

Rena l disorder and uro lit hiasis
Hyperuricemia and gout are frequently complicated by renal di sorder andurolithiasi s. For these comp lications, control of serum urate is known to be effective.
The major cause of the renal disorder and uro lithiasis is thought to be oversaturation ofurate in the urine, resulting in depos ition. The deposition can be effectively prevented
by decreasing the amount of urinary urate as a so lute, and increasing the volume ofurine as the solvent.

For patients with concurrent renal diso1·der, presence of urolithiasis, or ahistory of urolithiasis, allopurinol, the inhibitor of uric acid production, is to be
used. For patients with extent to a moderate degree of renal disorder,
co-administration of low doses of allopurinol (50-100 mg/day) and benzbromarone(25-50 mg/day) may be effective. For patients with renal dysfunction, the dose ofa ll opurinol should be adjusted based on the degree of renal dysfunction (see C hapter

111).
The urologic management for the reduction of urinaQ urate excretion is
performed b~ a low-purine diet and allopurinol treatment. Larger urine volume
increases the amount of urate dissolved in the urine, but can also affect the patient' s
quality of life. Thus, the patient should be instructed to intake water to maintain a urine
volume of 2,000 mL or greater per day. Water intake before sleeping and during thenight is especially important. Water intake should involve beverages that do not containalcohol or sugar.
The solubility of urate in the urine decreases with acidification urine, and theurine of gout patient often tends to be acidic. Correction of acidic urine is achieved
through dietary therapy or urine alkalizing agents. Table 8 shows a food that tends
to alkalize the urine. Urine alkalizing agents are the preparations of sodi um bicarbonate
or the citrate agents ; such agents should be taken at 1-6 g/day in 1-6 divided doses tomaintain a urine pH of 6.0-7 .0 (Ta ble 9).

2.

H ypertension and cardiovascular disorder sElevated serum urate, from the sta ndpoint of primary prevention and secondary

prevention, could be a risk factor for cerebrovascular and cardiovascular events. In

hypertensive patients, even after proper control of the blood pressure, elevatedserum urate level is likely to be a risk factor for cerebrovascular andcardiovascular events. In hyperuricemic patients with hyperten sion, the serum urate

19

levels thought to increase the ri sk of cardiovascular di sease are > 7.5 mg/dL in men and> 6.2 mg/dL in wo men.

Hypertension + serum uriate
level ~ 7 mg/dL

A nti-hypertensive agent that lowers urate level to contro lth e blood press ure to < 140/90 mmHg (lf 60 years old or
olde r, use the ta rget for elderl y patien ts)

Consider treatment if serum
ura te level ~ 8 mg/dL

Urate-lowering therapy andurinary tract management
based on disease typelf7 mg/dL < serum urate level < 8
mg/dL, improve li festy le andmonitor the course•...

Tendency to increase serum
urate level

Target serum urate level of s 6.0 mg/dL.
Consider the serum urate level that is related to cardiovascular events risk reduction(4.5 mg/dL < serum urate < 6.0 mg/dL fo r men; 3.2 <serum urate < 4.6mg/dL fo r women)

Figure 3

Treatment algorithms for hyperuricemia and concurrent hypertension

Table 8

Foods that tend to alkalize or acidify urine

Foods that tend to alkalize
urine

Alkalinity

Acidity

Foods that tend to acidify
urine

Hi h

Seaweed (hijiki, wakame)
Seaweed (sea tangle),
dried Chinese mushrooms,
Soybeans, Spinach
Burdock, sweet potato
CarrotBanana, aroid
Cabbage, melon
Japanese radish,turnip, eggplant
Potato, grapefniit

Eggs, pork, mackerel
Beef, trough shell
Bonito, scallop
White rice, yellowta ilTuna, saury
Horse mac kerel, saury-p ike
Sardine, flo underConger eel, Shiba shrimp

Low

Oriental shrimp(Excerpted fro m The Japanese Food Composition Table, 4th edi tion)

20

Table 9

Indication s of urine alkalization drugs for primary gout patients

I : relative indication
I plus one of 1-6 in U: mandatory indication
Acidic urine (urine pH < 6.0) and not improved by with dietary therapy
11
1. Patients with increased urate excretion in urine (::'.'. 800 mg of urate excreted inurine per day)2. Over-producers of urate
3. Patients estimated to have marked increase in urate pool in the body
4. Patients on uricosuric agents
5. Patients with current or hi story of urolithiasis
6. Patients suspected ofurate nephropathy (except renal failure)
Excessive alkalization of the urine can lead to lessen the solubility of calcium phosphate; thus,
ca reful attention is needed. Sodium bicarbonate can lead to sodium load, so careful attention should
be required for patients with heart failure , hypertension or renal dysfunction. Citrates have lower
sod ium load than sodium bicarbonate but contain potassium, and thus should be used with caution inpatients with renal dysfunction.
Table 10

Effects of anti-hypertensives on serum uric acid level

Anti-hypertensives

Effect on serum urate level

Thiazide diuretics

Increase~-blocker

Increase

a1-blocker

Decreasea/~-blocker

Increase

ACE inhibitor

Decrease

a-methyl dopa

No change

Ca lcium antagonist

Decrease

Losartan

Decrease

Other angiotensin II (Aii) receptor inhibitors

No change

Table 11

Treatment of hyperlipidemia in patients without complication otherthan hyperuricemia
Target serum lipid level

Serum total cholesterol
Serum triglycerides
Serum HDL-cholesterol< 220 mg/dL< 150 mg/dL;:: 40 mg/dL

21

The objective of blood pressure control in hyperuricemic patients complicatedwith hypertension is a blood pressure less than 140 mmHg/90 mmHg for patients aged
under 60 years, and a systolic blood pressure less than 150 (or less than 160 mmHg) for
patients aged 60 years or older (see The Guidelines of the Japanese Society ofHypertension) (Figure 3) . In selecting the hypertensive agent, it is preferable to use
antihypertensive drugs that also have urate-lowering actions (Table 10), such as
losa1·tan, angiotensin converting enzyme (ACE) inhibitors, long-acting calcium(Ca) antagonists, and a 1-blockers.
The

criteria

of

serum

urate

leHls

to

be

considered

to

start

anti-hyperuricemic treatment and target control levels follow the 6, 7, and 8 rules
specified by the Consensus Conference of the Society. These rules involve
evidence-based considerations for serum urate levels that represent a risk for
cerebrovascular or cardiovascular events, and the condition of serum urate levels
that reduce the development of those events.
In hypertensive patients, the major cause of hyperuricemia is based on theirunder-excretor type of urate, so uricosuric agents are primarily used. However, it is also
effective to concurrently use small amounts of uric acid production inhibitor(allopurinol).
Lt is impo1tant to select drug and determine the dosage, paying attention to dose
reduction of allopurinol based on the degree of renal dysfunction , and to the precautionsin the use ofbenzbromarone in patients with hepatic dysfunction .
3.

Hyperlipidemi aGreater importance is being placed on atherosclerosis as a factor in the

prognosis of hyperuricemic patients. For this reason , it is important to treat andcontrol hyperlipidemia.
However, although it is strongly suggested that higher urate level 1s an
independent risk factor for atherosclerosis, this has not yet been clearly established.
Thus, at this point, it is tlreferable that hyperlipidemia be treated according to the
Guidelines for Diagnosis and Treatment of Atherosclerosis Cardiov·asculardiseases of the Japan Atherosclerosis Socieh (Table 11) without considering theserum urate level. It is effective to use nictitate drugs in patients with complication of
hyperlipoproteinemia (a) (Lap(a)).
Some drugs for the treatment of hyperlipidemia can also affect the serum urate
level , so these effects also need to be taken into account (Table 12). Among these drugs,
fenofibrate used to treat hypertriglyceridemia have a strong uricosuric action and can22reduce the serum urate levels. Thus, this drug is especiall y effective for hyperuricemic
patients w ith under-excretor type of urate.
In order to identify any adverse drug reactions caused by anti-hyperlipidemic
drugs at the earliest stage, the patient should be periodically monitored by the tests forhepatic function, and peripheral blood together with the creatine phosphokinase (CPK)
assay.

Table 12

Drugs used in the treatment of hyperlipidemia

Generic name

Dose

Effect on serum urate level

HMG-CoA reductase inhibitor
pravastati n sodium
sim vastatin
fluvastatin sodium
atorvastatin

10-20 mg
5- 10 mg
20-60 mg
10-20 mg

None
None
None
None

Anion exchange resins
cho lestim id
cho lestyra mine

3g
8-12 g

None
None

Probucol500- 1,000 mg

None

Nicotinic acids
ni ceritrol

750-1 ,500 mg

Essentially none or slightincrease
Essenti all y none or slightincreaseni comol

600- 1,200 mg

Fib rates
fenofibrate
bezafibrateclinofibrate

200-300 mg
400 mg
600 mgclofibrate

750- 1,500 mg

Eicosapentaenoic acidethy l icosapentate
4.

1,800-2,700 mg

Decrease
None
Essenti ally none or sli ght
decrease
Essentia lly none or slightdecrease
None

Glucose intolerance and obesity
It is not negli gible in the effects of obesity on the cause or exacerbation fac tor ofhyperuri cem ia. In Japan , there has been an increase in obese patients due toovernutriti on, overeating, or unbalanced di et. Obesity has also led to the sim ultaneousdevelopment of hypertension , hyperlipidernia, g lucose intolerance or insulin resistancebeing invo lved with hyperuricemia, thus leading to the accumul ation of multiple risk

23

factors.

A.

Glucose intolerance
It is known that insulin resistance is observed in the early stages of obesity andthat the increase in serum urate is associated with hyperinsulinemia.
In diagnosing g lucose intolerance, plasma insulins are advised to measure
simultaneous ly in the oral g lucose tolerance test. The disease type of diabetes isdetermined by the blood g lucose levels based on the Classification and Diagnostic
Criteria of Diabetes Mellitus of the Japan Diabetes Society. There is no guidance forin sulin level , so the fol lowing cons iderations are given as an examp le.

(1) Patients without hyperinsulinemia
If the fasting insulin level is less than I 0 µU /mL and does not exceed a peak of
I 00 µU / mL after glucose loading, there is no complication with severe insulin

resistance. This includes patients without hyperinsulinemia and accumulation ofvisceral fat.
In such patients, glucose intolerance is not a cause of the increased serum urate
level, and dietary guidance for diabetes is given to correct the glucose intolerance. The
hyperuricemia is treated as usual.

(2) Patients with hyperinsulinemia
Insulin resistance can be diagnosed if the fasting plasma insulin level is greaterthan 10 µU/mL or the insulin leve l after glucose loading is greater than 100 µU /mL.
Many of these patients are also obese and can be observed by accumul ation of visceralfat.
In such patients, dietary therapy is instituted as well as a program of exercise
therapy . Weight reduction can lower or normalize the serum urate leve l, so it may not
be necessary to institute mate-lowering therapy. l f the rate of urate excretion does not
improve, then the primary underlying type is the under-excretor of urate . If the rate ofurate excretion normalizes but hyperuricemia still remains, then the underlying type isthe over-producer of urate. Urate lowering therapy being matched for the classificationof hyperuricemia is to be conducted .
For the treatment of diabetes mellitus, the appropriate treatment guidelines are
consulted.

If the glucose intolerance deteriorates and develops to the diabetic condition withovert glucosuria, then the renal excretion of urate increases and the serum urate level24

begins to fall. In such patients, if the underlying type of hyperuricemia is theover-producer of urate, then the urinary concentration of urate increases, so treatment
with a urine alkalizing agent alone may be preferable. If the patient already hascomplication with urinary calcu lus, a sma ll dose of uric acid production inhibitor is
used.
Jt is often difficult to differentiate whether the hyperuricemia has developed as aresult of glucose intolerance or that of primary hyperuricemia modified by glucose
intolerance. In such patients, the glucose intolerance should be treated first and then thehyperuricemia be corrected ; the application of urate-lowering therapy alone should be
avoided.
B.

Obesity
It has shown that the complication with hyperuricemia developed with theelvevation of body mass index (BMI). ln both subcutaneous-fat obesity and visceral-fat
obesity the incidence of hyperuricemia is hi gh, at about 70%. lt has been reported thatmost patients with visceral-fat obesity are the under-excretor type of urate, while in thecase of visceral-fat obesity, 31 % of patients are the under-excretor type of urate and
56% are the over-producer type of urate.
As with glucose intolerance, treatment is initiated after evaluating the contributionof obesity to the development of hyperuricemia in the patient. In some patients thehyperuricemia improves with weight reduction alone. Obesity treatment shou ld becond ucted after proper classification and diagnosis based on the guidelines of theJapanese Society for the Study of Obesity, and the treatment directed at the removal of
cause shou ld be initiated .
Rapid weight reduction can lead to cause hyperuricemja of over-producer type ofurate, which can deteriorate existing hyperuricemia and may cause a gouty attack . Thus,
it is someti mes necessary to use a uric acid production inhibitor.
In contrast to glucose intolerance, it is often difficult to correct obes ity. In
particular, those with severe obesity have much difficulty in weight reduction. As ameasure against gouty attack and renal disorder, it is often necessary to conductmate-lowering therapy along with weight reduction.
V.

Secondary Hyperuricemia and Its Treatment

1.

Over-producer type of urate in secondary hyperuricemia
Secondary gout constitutes about 5% of all gout patients. As with the primary type,patients can be classified into the over-producer type, under-excretor type and mixed

25

type of urate.
Ta ble 13 shows the various types of secondary hyperuricemia of theoverproduction type of urate.
A.

Treatment of underlying diseaselt is most important to treat the underlying disease, or eliminate or reduce the doseof the offending drug. In the diagnosis of hyperuricemia, one must alway·s look forpossible underlying causes. and it is important to search for them through medical
history , physical examination and general laboratory tests.
Table 13Over-producer type of urate in second ary hyperuricemia

I. Hereditary metabolic diseases
Lesch-Nyhan syndrome (hypoxanthine phosphoribosyltransferase[HPRT] deficiency)
5-phosphoribosyl-l-pyrophosphatase (PRPPase) overactivity
Congenital myogenic hyperuricemia
2. Increased cell proliferation
Hematologic malignancies
Acute
Acute le ukemia, malignant lymphoma
Chronic
Chronic myeloproliferative syndromes
Chronic myelogenous leukemia in chronic phase
Polycythemia vera
Essential thrombocythemia
Idiopathic myelofibrosis
Myelodysplastic syndromes
Solid tumors
Sarcoma, Wilms' tumor, small cell lung cancer,
breast cancer, seminoma, others
Acute tumor lysis syndrome
Non-neop lastic diseases Psoriasis vulgaris
3. [ncreased tissue destruction
Hemolytic anemia
Hypothyroidism
Rhabdomyolysis
Obesity
Exercise loading
4. Exogenous factors
High-purine diet
5. Drug induced
Anti-tumor agents
Mizoribine
Theophylline
Fructose, xylitol

26

B.

Treatment of hyperuricemia
The major component of treatment is the uric acid production inhibitor allopurino l.

Unti l the serum urate (crucial), urine vo lume, and urinary pH could be controlled,
treatment should be conducted along the lines of primary hyperuricemia and gout.

Depending on the status of the underlying disease. 1t ma) b1.: ncccssar) toadjust the therapeutic regimen including dose modification s. Once the underlying
disease has improved , allopurinol shou ld not be admin istered irresponsibly.
When allopurinol is used concomitantly with anti-tumor drugs, one should take
into account the poss ible drug-drug interactions. Careful attention should be taken whenallopurinol is used with agents that cause myelosuppress ion such as 6-mercaptopurine(reduce dose to about 1/3) and cyc lophosphamide (use with caution), and withpentostatin, which carries a risk of severe vasculitis.

C.

Treatment of gouty flare
Proceed as in the treatment of primary gout.

Note• Acute unc acid nephropathy and acute tumor lysis syndrome are diseases withmedical emergenci es, where the physician needs not only to adjust the serum urate levelbut also to in stitute systemic control.

Table 14

Mechanisms of mixed-type secondary hyperuricemia
Mechanism of overproduction of urate

Mechanism of underexcretion of urateType 1 glycogenosis

ATP deficiency

Hyperlactacidemia

Obesity

Increased lipid synthesis

Hyperinsulinemia

Toxemia of pregnancy

Tissue destruction ofplacenta etc.

Increased reabsorption inproximal tubules

Alcoho l consumption

Increased ATP
degradation and purine
intakeHyperlactac idemia

Nicotinic acid, nicotinamide

Increased PRPP synthesis

Inhibition of urate excretion

27

2.

Mixed-type secondary hyperuricemia
Table 14 shows the various types of mixed-type secondary hyperuricemia.

Treatment should be similar to that for primary hyperuricemia, taking into
account the features of both the over-producer type and the under-excretor type ofurate.

Table 15
Diseases(or pathophysiology) that induce hyperuricemia of theunder-excretion type of urate

3.

l. Primary

Cause unknown (idiopathic)
Familial juvenile gouty nephropathy

2. Secondary

Chronic renal disease (renal dysfunction)
Polycystic kidney
Toxemia of pregnancy
Lead nephropathy
H yperlactacidemia
Down's syndrome
Sarcoidosis
Type I glycogenosis (due to hyperlactacidemia)
Dehydration
Drugs
Diuretics (furosem ide, thiazide, 0-mannitol), low-dose
salicylate, pyrazinamide, ethambutol, nicotinic acid,ethanol (mediates hyperlactacidmia), cyclosporin

Under-excretion type of urate in secondary hyperuricemia
It is necessary to be versed in the diseases that can induce secondary

hyperuricemia with the under-excretion type of urate and their pathophysiology(Table 15) .
Secondary hyperuricemia associated with renal failure has been reported to have a
low incidence of gouty arthritis. In addition, there have been no consensuses on whether
hyperuricemia associated with renal failure promotes renal dysfunction or whether
hyperuricemia should be corrected from the viewpoint to preserve renal function . For
this reason, urate-lowering therapy is currently considered for renal failure patients as
fo ll ows:

28

I

Uric acid over-production states (n ucleotide synthetase deficiency etc.)2

Familial renal disease associated with gout and renal failure

3

History of gout

4

Patients with a persistently elevated serum urate level of9 mg/dL or greater.

In the treatment, uricosuric drugs such as probenecid and benzbromarone are
generally used . It is known that probenecid affects the metaboli sm of antibiotics andmany other drugs, so it is difficult to use this drug as a uricosuric agent. Thus, in dailyclinical practice, benzbromarone is used.
For the mixed type of over-producer and under-excretor of urate, it is often usefulto use benzbromarone concomitantly with the uric acid production inhibitor allopurinol.
However, as renal function declines, benzbromarone becomes less effective and iscompletely ineffecti ve in patients with renal failure at a creatinine clearance of 30
mL/min or less. Thus, in patients with renal dysfunction, allopurinol is indicated.
When allopurinol is used in patients with renal dysfuncti on, the bloodconcentration of oxypurinol, an active metabolite with a long half-life in blood,
increases, and serious adverse reactions of allopurinol may be seen in patients withrenal failure. For this reason , it is necessary to reduce the dose depending on the

degree of renal dysfunction (see Chapter 3).

Chapter VI.

1.

Lifestyle guidanceLifestyle guidance
With

the

realizationthathyperuricemia

and

gout

are

representative

lifestyle-related di seases, the role of lifestyle guidance becomes greatly expanded in a
non-pharmacological treatment aimed at improvement of lifestyles and habits. In thesetting of good patient-physician communication, the physician should counsel thepatient to identify problems of lifestyles that attribute to hyperuricemia so that thepatient positively incorporates the lifestyle guidance as a strategy of self-maganged careofhyperuricemia as a long-lasting chronic illness.

Table 16 shows the specific details of lifestyle guidance. Major objectives inlifestyle guidance for hyperuricemia are dietary therapy, restriction of alcohol
consumption, and recommendation of exercise.
A.

Dietary therapy
For the hyperuricemic patient with a tendency toward obesity, the primaryobjective of dietary therapy is the restriction of caloric intake along the lines suitable fordiabetes treatment. Reduction of obesity also leads to the improvement of visceral fat
accumulation and insulin resistance and improves the long-term prognosis of the29patient.
Purine rich diets are defined as those containing 200 mg or more of purines in I 00
g. Table 17 shows such diets ; namely, organ meats, dried fish, and other dried foods.
Dietary therapy should also incorporate restriction of excessive intake of purines.
However, except for hospitalized patients, it is almost impossible to maintain alow-purine diet on a consistent basis, and it is preferable to instruct simply to avoid
purine rich diets. A realistic goal is purines intake of not more than 400 mg per day.
Urologic management is important as well. Purine rich diets also tend to increase
the acid ity of urine, giving a further reason why dietary therapy should aim to restrict
such foods. Tn addition , to dilute the urinary concentration of urate, the patient should
aim to achieve a daily urine output of2,000 mL per day.

Table 16

Lifestyle guidance in hyperuricemia• Reduction of obesity• Dietary therapy
Restriction of high caloric intake
Restriction of purines intake
Intake of foods that tend to alkalize the urine
Sufficient water intake (to urine output of 2,000 rnL/day or more)• Restriction of alcohol intake
Japanese sake: I go ( 180 mL)
Beer: 500 rnL
Whisky: 1 double (about 60 mL)
No alcohol intake in 2 days/week or more
• Adequate exercises
Aerobic exercise• Reduction of stresses

30

Table 17

Foods with high or low purine content

Extremely high(> 300mg/ I OOg)

Chicken liver, dried true sardine, milt of grunt, monkfish
liver steamed with Japanese sake, dried bonito flake,dried sardine, dried shinese mushroom

High (200-300 mg/I OOg)

Pork liver, beef liver, bonito, sardine, oriental shrimp,
dried horse mackerel , dried saury

Low ( 50-100 mg/ l OOg)

Eel , smelt, pork loin, pork ribs, beef sirloin, beef ribs,
beef tongue, mutton , ham , pressed ham , bacon, mincedfi sh dumpling, spinach, cauliflower

Very low (< 50 mg/l OOg)

Corned beef, fish sausage, kamaboko (boiled fish paste),chikuwa (roasted fish paste), fried fish paste, herring roe,salmon roe, wiener sausage, tofu, milk, cheese, butter,
eggs, corn , potato, sweet potato, rice, bread, udon (wheat
noodles), soba (buckwheat noodles), fruits , cabbage,
tomato, carrot, Japanese rad ish , Chinese cabbage, hijiki(seaweed), wakame (seaweed), sea tangle(Converted as total purines)

B.

Restriction of alcohol intake
Even alcoholic beverages containing less purines affect purine metabolism (bypromoting the degradation of endogenous purines and reducing urate excretion via thekidneys) and increase the serum urate level, so excessive intake of any type of alcoho lshould be restricted. Beer not only contains large amounts of purines but also has
relatively high caloric contents compared to other types of alcoholic be verages, and thus
promotes obesity. It is considered that the effects of a lcohol on serum urate begin toappear with an intake of about 180 mL of Japanese sake, 500 mL of beer, or 60 mL ofwhiskey.
C.

Recommendation of exercise
Counseling in exercise therapy 1s necessary for obese patients, but cardiac

function shou ld be evaluated prior to initiation. Excessive exercise should be avoided. It
is desirable to achieve a program of light exercise at least 1 hour after meals every day
to the target body weight (BM! of less than 25kg/m 2 ).
Aerobic exercise has no effect on serum urate level but improves the various
physical conditions that are associated with hyperuricemia by reducing body fat,
improving mild cases of hypertension, increasing HDL cholesterol , and improving
g lucose tolerance.

31

Note
• Patients often strictly follow the prescribed caloric, purine and alcohol restrictions fora short period of time but most of cases result in leading to rebound . The physician
should repeatedly explain the patient that obesity, purine rich diet and habitual alcohol
intake are harmful , so that the patient becomes motivated to follow the treatment
program. This comment also applies to exercise. The initial goal should be to achieve
the habit ofregular exercise, and after establishing that without stress, then the details of
the exercise can be modified through consultations.

32Committee for the Preparation of Guidelines for theManagem ent of Hyperuri cemia and GoutCommittee for t he Preparation of
G uid elines for the Ma nagement ofHyperurice mia and Gout
J apa nese Society of Go ut a nd Nu cleic
Acid Meta bolism• Committee C ha ir

Tatsuo Hosoya

Hiromu Nakajima

Div ision of Kidn ey and Hypertension,(Nephrology & Rh eumatology), Departm ent
ofintem al Medi cine,
Jikei Uni versity School o f Med icne

Department of Clin ica l Laboratory, (InternalMedi cine on End ocrino logy & M etaboli sm)
Osaka Medi ca l Center fo r Ca nce r and
Ca rdi ovascul ar Diseases (OMCC)

Ichiro Hisatom e• Co mm ittee M e mb e rs

Takanori Ueda
Department of Interna l Medicine 1(Hemato logy & Oncology), Facul ty of
Med ica l Sciences, Uni versity of Fukui

Naoyuki Kam atani
Institute of Rheumato logy,
Toky o Women 's Me di cal University

Hiromu Nakajima
Department of C lini ca l Labora tory, (Interna lMedi c ine on End ocrino logy & Metabolism)
Osa ka Medical Center for Cancer andCard iovasc ular Di seases (OMCC)

Ichiro Hisatome
Division of Candi ology, Department of
Card iovascular Intern al Medi cine,
Tott ori Univers ity Hospital

Shin Fujimori
Department of Interna l Medi c ine,
Teikyo Uni versity Schoo l of Medi cine

Hisashi Yamanaka
Institute of Rheumato logy,
Tokyo Women's Medi ca l University

Tetsuya Yamamoto
Department o fTntern al Medi cine,(Endocri nology & Metabo lism),
Hyogo Co llege of Medic ine• A utho ri ng Membe rs

Takanori Ueda
Department oflntern al Medi ci ne 1
(Hemato logy & Onco logy), Fac ulty of
Medical Sciences, Uni vers ity of Fukui

lwao Ohno
Division of Kidn ey and Hypertension,(Nephro logy and Rh eumato logy)
Jikei Uni ve rsity School of Medi c ine

Department of Cardiovascular Intern a l
Medicine Cardi ology,
Tottori U niversity Hospital

Shin Fujimori
Department of ln te ma l Medi cine
Metabo lomics,
Teikyo University Schoo l of Med icine

Tatsuo Hosoya
D ivision o f Kidney and Hypertension,(Neph ro logy & Rheumato logy), Department
of Intern al Med icine,
J ike i Uni ve rsity Schoo l of Medi cine

Hisashi Yaman aka
Institute of Rh eumatology,
To kyo Women' s Medi cal Univers ity

Tetsuya Yam amoto
Departm ent of In tern al Medi cine,(End ocrin ology & Metabo lism),
Hyogo Co llege of Medi cine
• A d v isor

Takuo Koide
Department of Uro logy,
Osa ka Koseinenkin Hospi tal• Secretariat

lwao Ohno
Di vision of Kidney and Hypertension,(Neph rology & Rheumato logy),
Jike i Univers ity Schoo l of Medi cne• Evaluation Members

Mitsuo Itakura

Yuji Matsuzawa

Division of Genetic Information ,Institute for Genome Research,
The Uni versity ofTokushima

Kazuhiko Ito

Department of Internal Medicine andMolecular Science,
Graduate School of Medicine,
Osaka Uni versity

Health Care Management Center,
Mitsubishi Electric Corporation

Toyokawa C ity Hospital

Yoshifuji Matsumoto

Harutoshi Kizaki

Yoshiro Wada

Department of Biochemistry,
Tokyo Dental College

Nagoya City University

Norio Kohno
Schoo l of Allied Health Sciences,
Schoo l of M edicine, Osaka U niversity

Masataka SasadaCollege of Medical Technology,
Kyoto University

Yohei Tofuku
Ishikawa Sa iseikai Kan azawa HospitalKu suki Nishioka
lnstitue of Medical Scienses,
School of Medicine, St. Marianna University

Toshikazu Hada
Department of Internal Med icine,
Hyogo College of Medicine

Guidelines for the Management of Hyperuricemia and Gout (Abridged
Edition)September I, 2002

First print ing of fi rst editi on

Edited by: Committee fo r the Preparation ofGui delines for the Management of Hyperuri cemia and
Gout
Publi shed by: Japanese Society of Gout and Nucleic
Acid Metabo lism3rd Floor, Nishi-Shimbashi Fukutoku Bldg., 1- 11 -5
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