ADA Deficiency Book - A5

Transcription

Gout Booklet 2008 - Text:ADA Deficiency Book - A5
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Contents
GOUT AND KIDNEY DISEASE: OVERVIEW
Professor J Stewart Cameron ............................................................................................ 4
WHAT IS THE RELATIONSHIP BETWEEN GOUT AND KIDNEY FAILURE?
Dr G Venkat-Raman .......................................................................................................... 7
HOW DO WE CONFIRM THE DIAGNOSIS OF GOUT?
Dr Terence Gibson .......................................................................................................... 10
HOW DO WE CONFIRM THE DIAGNOSIS OF GOUT IN THE LABORATORY?
Dr Lynette Fairbanks ........................................................................................................ 12
GENETICS OF ADULT GOUT
Dr Tony Marinaki ............................................................................................................. 16
WHAT ADVANCES HAVE THERE BEEN IN TREATING GOUT
IN ADULTS WITH RENAL DISEASE?
Prof J Stewart Cameron .................................................................................................... 17
INSTRUCTIONS FOR A LOW PURINE/CAFFEINE FREE DIET .......................... 24
DIETARY PURINE CONTENT OF FOOD ................................................................. 26
SUGGESTIONS FOR FURTHER READING ............................................................. 28
CONTACT ADDRESSES FOR FURTHER HELP....................................................... 30
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Gout and Kidney Disease: Overview
J Stewart Cameron
This booklet deals with a subject which lies in the background of much work done
by PUMPA: gout itself. We are familiar with gout arising from inherited disorders such
as HPRT deficiency and the Lesch-Nyhan syndrome, PRPP synthase overactivity,
and FJHN, on two of which PUMPA has already prepared and circulated booklets.
Here we look at the much commoner,
“usual” or ordinary form of gout, but
particularly (remembering FJHN) in
relation to kidney problems and kidney
disease. Gout has long been known to be
a disease of plenty, uncommon in hard
times with famine, and associated with
good - perhaps too good - living. But it
also has a genetic component: gout runs
in families, even those without any of the
single-gene
inherited
disorders
mentioned above, which the purine
laboratory has studied so carefully.
Why do people get gout? The answer is well
known to PUMPA members - because uric acid
(or more accurately, urate salts) form crystals in
the tissues of the joints, kidneys and elsewhere.
Urate in humans is the end-product of purines
in food and in metabolism within the body, so
both intake of purines in food and tissue
breakdown within the body contribute to its
generation. Urate is relatively insoluble in water
and body fluids, and the concentration of urate
in blood plasma is near the limit.
One would expect, perhaps, that urate being
4
Diet Metabolism
Purines
(DNA, ATP etc.)
Xanthine
Urate
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rather toxic, would be got rid of efficiently through the liver or the kidney (which are
the two principal organs of disposal in the body). In fact the liver gets rid of no urate
at all, and the kidney, having filtered the urate very successfully from the plasma, then
takes most (about 88% in healthy adults) back again into the body through the kidney
tubules, leaving only 12% (the fractional excretion of urate, or FEur) to pass into the
urine. This peculiar behaviour renders humans liable to gout.
Common adult gout is a “kidney disease” - in that in the re-absorption of urate by the
million tubules in each kidney is greater than usual - on average above 90%, often
95% (FEur 5-8%). This sets the scene for a higher plasma urate. In each cell of the
tubule there are many channels and exchangers that transport urate both ways into
and out of the cell, but the main transporter lies in the first part of the tubule, which
re-absorbs filtered urate and is called URAT-1. Whether the differences between
gouty people and those without gout lies in abnormal function of this absorption, in
one of the other minor mechanisms of urate transport, or both, we do not know yet.
Also on the basis of the two
ancient observations on plenty
and family mentioned above,
modern investigation leads us to
believe that “usual” gout is the
result of inheriting a number of
genes which program the kidney
to absorb more urate than average.
If on top of this, purine intake in
the diet is high, then plasma urate
rises above the critical level, and
gout attacks follow.
GLOMERULAR
FILTER
URAT-1
82 - 92%
Gout 92 - 95%
8-18% Gout 5-8%
100%
TUBULAR
CELL
URIC ACID EXCRETED IN
URINE
Why do men get gout rather than
women? And why is gout rare in
children and young adults, unless they have one of the inherited disorders of purine
metabolism or transport well known to PUMPA members? Because women
normally have a lower re-absorption of urate in their kidney tubules, giving a higher
FEur (15% or more). This difference runs only from menarche to menopause
(suggesting it is the result of hormonal influences), so older women are indeed
vulnerable to gout also. All children have a very low re-absorption, and
correspondingly a high FEur (~25%). Why are joints affected so frequently rather
than somewhere else in the body? That remains a mystery…
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There is one other abnormality of kidney function that gouty people have, which is
important because it leads them also to form kidney or urinary tract stones, made of
uric acid. These are usually of uric acid and not urate salts, because gouty patients
pass rather acid urine all through the day, unlike normal people, who pass less
acid urine, peaking in the afternoon. We do not have an explanation for this finding
as yet. The more concentrated the urine (as in hot climates) the more likely stones
are to form.
The treatment of gout depends upon all this knowledge. The goals of treatment
therefore are to limit tissue breakdown, decrease purines in the diet, increase the
excretion by the kidney, and drink a lot of water to make sure the uric acid stays
dissolved in the urine.
A final oddity, which will be touched on by Dr Venkat Raman below, is that until 50
years ago, gouty patients not only got stones in their kidneys, but also frequently
formed crystals in their kidney tissue with inflammation and damage (“gouty
nephropathy”). Today these events are rare, unless an inherited disorder is found to
underlie the gout. The full reasons for this fortunate change are not known, but could
relate to the introduction of effective treatments for high plasma urate concentrations
in the 1950s and 1960s.
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What is the relationship between
Gout and Kidney Failure
Gopalkrishnan Venkat-Raman
History
Gout was described first by Hippocrates (‘Father of Medicine’) as long ago as 5th
century BC, and has been recognised as a clinical entity by eminent physicians ever
since. The modern history of gout began with Thomas Sydenham, who defined gout
in 1683 - based on personal symptoms! The high uric acid level in the blood
(hyperuricaemia) which underlies gout was discovered by Garrod in 1848. Purine
synthetic pathways and enzymes were elucidated in the 1950s and the first enzyme
defect causing gout was identified in 1966.
Demography and prevalence
Gout is a disease of the rich and famous, of royalty, power and genius, primarily
affecting adult males (>90% of cases). There is considerable interregional and
international variation, with only 0.3% of the population affected in Europe and
America, but as many as 10% of male Maoris in New Zealand.
Clinical manifestations
• Gout - or more exactly monosodium urate crystal deposition disease - is
characterized biochemically by ‘supersaturation’ of the body fluids outside its cells.
This results in recurrent attacks of acute inflammatory arthritis.
• Untreated, this may progress to accumulation of urate crystals to form ‘tophi’
• Uric acid kidney stones may form in some people.
• Nowadays, kidney disease in gouty patients is most often due to associated diseases,
because of the ready availability of treatment for gout.
Acute gouty arthritis, usually affects only a single joint, mostly at the base of the great
toe, followed by a knee. Blood uric acid is usually - but not always - high. Recovery
from attacks is complete in a few days. A number of factors predispose to acute gout,
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namely, trauma, starvation, dehydration, diet (meat & fish), alcohol and some
medicines (e.g. thiazide diuretics).
Interval/intermittent gout is characterized by recurrent attacks of variable frequency.
If untreated, intervals shorten progressively, and can ultimately lead to chronic an
arthritis which eats into the surrounding cartilage and even bone. Today, chronic
tophaceous gout is seen only in patients not treated (or in those who are unable to
tolerate the medications). These tophi may become widespread.
Uric acid stones account for 5-10% of all kidney stones in Europe and USA, but may
exceed 40% in hot, arid climates where urine volume is low, and the acid urine
promotes uric acid precipitation. Prevalence among patients with gout (prior to
treatment) was high - up to 20%, but is rare these days. The three major risk factors
for urate stone formation are: increased uric acid excretion, reduced urine volume
(not enough fluid intake) and an acid urine.
KIDNEY DISEASE AND GOUT
Several different forms of kidney damage may be seen in gouty patients.
Chronic urate nephropathy
Kidney function impairment is common among patients with gout, but usually reflects
the presence of other disorders such as hypertension, diabetes mellitus, obesity or
disease of the arteries to the kidney in addition. However, rarely in chronic untreated
gout, urate may deposit in the substance of the inner portion of the kidney, leading to
a chronic inflammatory reaction, and varying degrees of fibrosis, described as
“chronic urate nephropathy”. This sequence of events can lead to renal failure, but
can generally be controlled or even reversed in part by allopurinol.
High plasma uric acid levels (hyperuricaemia) and kidney failure
This is a frequent association which begs the question of which is the chicken, and
which the egg. Current evidence suggests that hyperuricaemia in itself does not
augment progression of the kidney failure. Equally renal failure does not often cause
gout (though hyperuricaemia may be present).
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Acute uric acid nephropathy
Gout occurs rarely in the acute hyperuricaemia that follows massive cell destruction
- for example following chemotherapy for leukaemia. A kidney biopsy, if necessary,
will show evidence of uric acid crystals in renal tissue.
Familial nephropathies and uric acid
A number of overlapping syndromes with genetic mutations have been described,
some being associated with hyperuricaemia or/and gout. ‘Familial juvenile
hyperuricaemic nephropathy’ (FJHN), is characterised by gout at a relatively young
age, unusually affecting both sexes and leading to progressive renal failure. More
recently it has been linked to a genetic abnormality of production in the kidney of a
urinary protein called uromodulin (see PUMPA booklet on FJHN).
Specific enzyme defects, such as HPRT deficiency (see PUMPA booklet), have been
described which can cause gout, without significant kidney involvement, and for that
reason pose less of a challenge, though the control of gout can sometimes be
extremely difficult in some patients.
Treatment
Gout should be treated in the usual way, whether or not there is renal failure. Drugs
used are covered elsewhere. If gout or severe hyperuricaemia is the cause of renal
failure, then effective treatment can halt the progression of kidney disease. However,
there is no evidence that treating hyperuricaemia (without gout) is of benefit in
slowing the progression of renal disease caused by other diseases.
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How do we confirm the diagnosis of Gout?
Dr Terence Gibson
Gout is beloved by cartoonists because it is easy to caricature the archetypal patient.
He is usually a man in middle life, overweight and given to drinking lots of alcohol.
In a previous age, when fatness and access to lots of food and drink were signs of
wealth and success, the swollen and exquisitely painful big toe, foot or ankle was an
object of hilarity and derision to the less affluent majority. As easier access to cheap
food and alcohol expanded across the social spectrum, the idea that gout was a joke
wore a bit thin. It has steadily increased in the relatively rich countries of the West.
Thus the story of painful swelling of a foot or ankle that comes and goes in a man is
recognized as evidence of gout by even a lay person (Fig). Such a picture requires no
investigations and most doctors are capable of a clinical diagnosis of gout based on
such a typical history in the appropriate setting.
Typical
Gout
Tophus
Could
it
be
Gout
Tophus
Tophi
Tophi
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Sudden pain and swelling of
the knee joint in a man with
acknowledged gout or
previous symptoms affecting
the foot is also likely to be
gout but the number of
possibilities is broader. It is
swelling of the knee that
invites examination of joint
fluid under the microscope
for the crystals of uric acid.
Confirmation of gout in this
fashion is the only way of
establishing an unequivocal
diagnosis. Identifying urate
crystals in synovial fluid
from any affected joint or
from scrapings of surface
deposits of uric acid (tophi)
puts the diagnosis beyond
question. Examination of
joint fluid also excludes the
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other two main causes of isolated hot swollen joints namely pseudogout and
infection. In all three conditions there may be fever, a rise in the circulating white cell
count and pronounced elevation of blood markers of inflammation. The appearance
of the fluid is useful.
A joint that becomes swollen as a result of a sprain, injury or osteoarthritis contains
clear fluid whereas one that is inflamed will yield a cloudy sample. Examination
under a microscope is then required to identify and distinguish urate crystals from the
calcium pyrophosphate crystals that cause pseudogout. When no crystals are seen in
a very cloudy sample, infection is possible. A raised blood uric acid level is not
diagnostic of gout. It is seen in many people who do not have arthritis and can be
elevated by alcohol, kidney impairment, diuretic treatment and small doses of aspirin.
There is a relationship between high uric acid levels, obesity and high blood pressure.
The higher the level the more likely is it that gout will occur at some time, but in acute
gout the level can be normal and that is why examination of joint fluid and tophi can
be so important. There is no compelling case for treating a high blood uric acid level
in the absence of gout although recent claims have revived the argument that a high
uric acid level is an independent risk factor for heart and kidney disease.
So far, so good. The diagnosis is not always that simple and with ageing, diuretic use
and kidney failure, gout can present in unusual ways. In renal failure, a high blood
uric acid is common but typical gouty arthritis occurs less often than expected. It is
possible that the severe inflammation of acute gout is suppressed by products which
can no longer be excreted by the damaged kidneys. Older persons may also develop
tophi without any gouty arthritis. These occur on their elbows, ears, Achilles tendons
and especially over the terminal finger joints where there may be pre-existing
osteoarthritic swellings called Heberden nodes (Fig). Sometimes the tophi ulcerate
and discharge uric acid paste-like material resembling pus. Many of these cases are
thought initially to have local infections and are treated inappropriately with
antibiotics. A chronic deforming arthritis can also develop in these patients due to
tophi within and around the joints, causing deformities. This may look like
rheumatoid arthritis from which it may be difficult to distinguish, especially when
tophi occur on the elbows resembling rheumatoid nodules (Fig). during treatment
with blood uric acid lowering drugs like allopurinol, tophi begin to disintegrate and
ulcerate or discharge through the skin. This is a good sign but is sometimes viewed
with alarm and often treated as an abscess.
In summary, typical gout of the foot is easy to recognise but in older people, amongst
those on diuretics and in the face of renal failure, the features are often atypical. The
only way of establishing a confident diagnosis is the identification of urate crystals
under a microscope.
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How do we confirm the diagnosis
in the Laboratory?
Dr Lynette Fairbanks
The first question for the laboratory when referred a patient with gout must be - Is
there is an underlying genetic defect causing the raised uric acid?
To answer this question, uric acid concentrations must be measured in urine, as well
as blood (plasma). These measurements are essential to exclude any known genetic
metabolic disorders that may present first as gout in children and young men, as well
as in middle -aged males.
The latter include Familial Juvenile Hyperuricaemic Nephropathy (FJHN). FJHN has
been the subject of a previous PUMPA booklet and is clearly a complex disease with
multiple genetic causes, all having much the same clinical presentation - a raised
plasma uric acid. Moreover, the latter is often, but not invariably, associated with
gout, not only in young men, but also in women, and children of either sex.
However, unlike adult gout, FJHN is generally coupled with the early onset of severe
renal disease.
There are several other possible genetic causes of gout, which also need to be
excluded first - especially if the patient is male (see PUMPA booklets “Caring for
Children with Lesch-Nyhan Disease” and “Caring for Patients with FJHN”).
Gout can be the hallmark of other genetic disorders as well, some of which present
first with kidney disease and/or kidney stones, due to the sheer insolubility of uric
acid in urine - especially when the acidity is high - i.e. the pH is low and the urine
more acid than alkaline.
Importantly, adult gout differs from the other forms of inherited gout above, which
result from uncontrolled uric acid synthesis by the body, resulting in genetic overproduction, when the amount of uric acid excreted in the urine is raised compared
with normal, as well as the plasma uric acid being high.
In adult gout by contrast, the uric acid in the blood is indeed raised, but this results
from a lower than normal excretion by the kidney. Consequently, the first important
criteria for diagnosis to exclude genetic disorders in adults who present with gout, is
that urine uric acid must always be measured, as well as plasma uric acid.
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How do we measure uric acid accurately in blood and urine?
This is another problem. Uric acid is extremely insoluble outside the body, and, for
example, will precipitate from urine on cooling - especially if the urine is acid and has
a low pH. Consequently, all urines must be examined for crystals, both in the urine,
or sometimes adhering to the plastic bottle used to collect the sample. To overcome
this problem all collection bottles must be examined and if necessary stood in a sink
of hot water (ca.56oC) for around 30mins, shaken vigorously, examined and then
warmed if necessary to ensure solution of all crystals and examined again before
recording the volume. A small sample (aliquot of 5-10 mls) can then be taken, placed
in a small sterile plastic Eppendorf tube and stored in a freezer at -20oC, if immediate
measurement is impossible.
Uric acid (or rather sodium urate) in plasma extracts and uric acid in urine is
measured in the laboratory by a specific method using an enzyme called uricase.
Uricase converts uric acid to allantoin, which is a non-UV-absorbing compound, and
the method is thus very specific. The amount of uric acid in the plasma extract, or in
a well-mixed aliquot of urine, is calculated by measuring the absorption in ultra-violet
(UV) light, in a spectrophotometer. Urate (like many chemical compounds) has a
characteristic absorption spectrum in UV light, so the conversion of urate to a nonUV absorbing compound by uricase can be measured accurately, which is a sensitive,
as well as a specific method.
The FEurate mentioned above (see Cameron) is the crucial measurement. It is
obtained by measuring the uric acid in a urine collected over 24h (or a shorter
specific timed collection), dividing this value by the plasma concentration, then
factoring it by parallel measurements of creatinine, and the result expressed as a
percentage (%). The FEurate varies with age and sex in normal subjects, but is
universally low in patients with adult gout. The importance and usefulness of the
FEurate is that, unlike both plasma urate concentration and 24 hour uric acid excretion,
it is INdependent of the intake of purine-rich food in the diet, since urine urate is
divided by plasma urate to obtain the result.
What values do we get in normal people compared with those
with adult gout?
The values for uric acid concentrations in plasma, and its excretion in the urine, vary
widely in normal healthy people, depending on local dietary habits, being much
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higher in France, the USA and Australasia than in the UK. Thus normal ranges must
be developed first in each country, or ethnic group, by measuring uric acid (UA) in
blood and urine of healthy individuals.
The first step is to measure the uric acid concentration in the blood (plasma), and
urine if necessary, with the patient consuming their normal diet. If either value is
high, measure blood and urine uric acid again after asking the patient to adhere to a
low Purine diet for at least three days, as listed on the diet sheet that you can give them
(see p24).
This combination of studies is necessary first to exclude a genetic Purine enzyme
defect as the cause of the excess uric acid (e.g. HPRT deficiency, or PRPPsynthetase
superactivity (PRPS) - see previous PUMPA booklet. Caring for patients with LND.
The values listed below are for the UK, and do not apply to other countries. They
were derived by measuring UA in blood and urine of healthy individuals eating a
normal UK diet (which is generally low in purines - i.e. one meat meal per day, and
no offal. Values for the same group of subjects in France, for instance, would be much
higher in some areas, due to the high consumption of seafoods, paté and offal).
NORMAL RANGES FOR URIC ACID/URATE IN THE UK POPULATION
Plasma UA
(µmol/l)
female
male
male gout
222 ± 42
261 ± 41
Urine UA
(mmol/24h)
2.7 ± 0.5
3.0 ± 0.5
FEur
12.8 ± 2.9
8.1 ± 3.2
5.4 ± 1.4
It is evident immediately that plasma uric acid concentrations in the healthy UK
population are lower in women than in men. This is reflected also in the figures for
their FEurate (FEur), which are lowest in men, higher in women (and highest of all in
children - not shown. See FJHN booklet). Importantly, male patients with adult gout
have a much higher plasma uric acid, associated with a much lower mean Feurate of
5.1%, which explains their tendency to gouty attacks.
Adult gout must be distinguished also from other known disorders which present as
gout, one of them being Familial juvenile hyperuricaemic nephropathy (FJHN), the
subject of a previous booklet. FJHN is clearly a complex disease with multiple genetic
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causes, all having much the same clinical presentation - a raised plasma uric acid is
often, but not invariably, associated with gout in young men. The difference is that
women, and children (of either sex) may also be affected and FJHN may be coupled
with the early onset of severe renal disease as well.
Clinical laboratory diagnostic approach
The first step in order to establish a diagnosis of gout is to measure the uric acid
concentration in the blood (plasma), and also the urine, when the patient is eating
their normal diet. If either result is high, the uric acid concentration in blood and urine
uric acid should be measured again after the patient has adhered to a low purine diet
for at least 3 days. Instructions are listed briefly on the diet sheet p24, which can be
given to the patient.
The above combination of studies is essential to detect (or exclude) the minority of
gouty patients who have inherited a genetic purine enzyme deficiency which results
in excess uric acid production. Two such genetic metabolic defects have been found
which are associated with elevated uric acid concentrations in blood and urineHPRT (hypoxanthine phosphoribosyltransferase) deficiency, and PRPS
(phosphoribosylpyrophosphate superactivity). Both have been described in previous
PUMPA booklets.
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Genetics of Adult Gout
Dr Tony Marinaki
Gout has a genetic basis. In the very rare cases arising from the overproduction of uric
acid, gout is due to a genetic defect in either of the X-linked genes HPRT or PRPS.
The nature of the genetic defect in these cases leads to some functional impairment
of enzyme activity; however the enzyme works sufficiently well to protect the patient
from the neurological symptoms usually associated with these metabolic disorders.
Inheritance follows the maternal lineage, and severe gout may occur on the mother’s
side of the family.
Much more common is the type of gout due to the under-excretion of uric acid. Often
patients will comment that their father had gout, ruling out an X-linked pattern of
inheritance. Although gout is relatively common in the populations and seems to run
in families, pattern of inheritance is not straight forward. This suggests that multiple
factors in a person’s genetic background predispose to uric acid under-excretion and
these interact with environmental factors such as diet, resulting in gout.
Recent research has sought to unravel the genetic
factors predisposing to gout. A group in Dresden
were the first to show that normal genetic variation
(or polymorphisms) in the gene encoding human
urate transporter 1 (hURAT1) which is a member of
a family of organic anion transporters is associated
with hyperuricaemia due to uric acid
underexcretion. There are a large number of different transporters expressed in the
kidney and the function of many of these is poorly understood. It seems likely
therefore that normal genetic variation in some of these transporters may also
contribute to hyperuricaemia and ultimately, predispose to gout.
In a few years it will possible to define a genetic profile which carries a high risk of
gout. This raises the question of whether testing for these genetic markers in the
general population will be useful to patients. It is possible that knowing from the age
of 30 years for example, that you have a genetic profile predisposed to developing
gout, would encourage patients to make lifestyle changes delaying or preventing the
onset of gout.
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Treatment of Gout in Kidney
Disease and Kidney Failure
J Stewart Cameron
Introduction
As we have learnt from Dr Venkat Raman (above), kidney disease due to gout is rare
today in the “usual” gout, found mostly in middle-aged males. Moreover, kidney
disease and renal failure is not often associated with clinical gout, except in
inherited disorders of purine metabolism or transport, such as HPRT deficiency or
FJHN, which previous PUMPA booklets have dealt with. Furthermore, the latter are
usually children or young adults. In older adults, intoxication with metallic lead may
also bring about both maladies together. This poisoning may not be obvious or be
recorded, and must not be forgotten if someone suffering from both kidney failure
and gout is encountered, and no inherited disorder is present. Lead is still a potent
cause of kidney failure and gout in the developing world, as industrialisation (and
pollution) begins. If it is found, it will need treatment, which lies outside this
booklet’s scope.
The kidney responds to a decline in the filtration rate by increasing the proportion of
urate filtered which can escape into the urine (the fractional excretion of urate, or
FEur mentioned above). nevertheless the plasma urate concentration is always raised
to some extent in patients with poorly functioning kidneys. Why this is not followed
by gout as frequently as it is in those without renal failure, is not known - it may have
to do with the depression of inflammatory responses to urate crystals in tissue by the
uraemic state, as Dr Venkat Raman discusses.
We must not forget one very large group of people with reduced kidney function the elderly, even when otherwise apparently healthy. Kidney function (like all body
functions!) falls off with age in the great majority of people, and this is worse if high
blood pressure, or blood vessel disease, is present also. Thus about 15% of the whole
population in developed countries have lower kidney function than normal,
compared with young healthy adults, and may present with similar problems to
younger people with actual kidney diseases.
Gout in people with kidney failure may not be the typical gout described above,
affecting mainly the peripheral joints in the lower half of the body. Sometimes the
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lumps of urate in the soft tissues (tophi) are the first thing the person notes without
any arthritis, or the gout is in large joints anywhere in the body.
Treatment of acute gout in the presence of kidney disease:
general issues
The treatment of gout falls into two phases: the immediate treatment of an acute
painful attack of gout, and the long-term management of intermittent or recurrent
gout. Obviously in managing gout in the presence of kidney disease, one starts with
what is available for “simple” gout in those with normal kidney function. Surprisingly
for such a common disease, the information available on how best to treat acute and
recurrent gout is not at all clear. This is in part because most treatments commonly
used today were introduced 40-50 years ago, when standards of evaluating
treatments were lower and less well developed than today, and further studies have
simply not been performed to answer a number of important questions.
Unfortunately also, a number of the medicines which seem to be of great help in gout
have extra problems, or are difficult to use, if kidney disease is found also. This makes
the management of gout in the presence of kidney disease more difficult and more
complicated.
The acute gouty attack in someone with kidney problems
The intense pain of gout has been described as one or the worst that can be
experienced, and although “ordinary” painkillers may be sufficient, the pain may on
occasion justify the (temporary) use of even strong opiate drugs such as morphine.
Local treatments such as resting and protecting the joint from pressure, as well as
using cold, have been demonstrated to be effective. Cooling can be by using ice in
bags, or frozen peas as a flexible dressing - BUT these should be kept directly off the
skin by a plastic covering, to avoid cold “burns”.
In terms of obtaining a specific effect against the acute inflammation of gout (apart
from the pure analgesics (painkillers), such as morphine, the usual recommended
medicines are:
(1) NSAIDs (Non Steroidal Anti Inflammatory Drugs) such as the familiar
ibuprofen - which is however itself too weak to be of much use in gout naproxen or a variety of others safer in avoiding stomach irritation or even
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bleeding, such as celecoxib (Celebrex). Unfortunately all NSAIDs reduce the
already compromised filtration in the kidneys still further, and need to be used
very cautiously or not at all in people with kidney problems.
(2) Colchicine. This is extracted from the autumn crocus bulb (colchicum
autumnale) and has been used for gout attacks for almost 2000 years.
Unfortunately, it also has problems in people with kidney disease, as it usually
causes diarrhoea if it is to be effective. Kidney failure also enhances the risks of a
rare and serious, sometimes fatal neurological complication of the drug.
Cochicine is also slow to have an effect, taking days rather than hours - not good
if you are in excruciating pain!
(3) Corticosteroids such as prednisolone. These have the advantage that, as well as
being taken by mouth, they can be injected directly into the joint if it is a large one
(e.g. an ankle or knee) in the form of hydrocortisone, allowing immediate relief
also of the intensely painful pressure within the inflamed joint. Although toxic
when given over longer periods - and thus not used in gout in this way corticosteroids are the treatment of choice for the acute attack of gout in those
with kidney problems.
Chronic intermittent or “interval” gout with kidney
problems; difficulties in treatment
Lifestyle and diet
As with all types of gout, life style affects strongly the development or frequency of
gouty attacks: important factors include attaining and maintaining a normal body
weight, best judged by the BMI (body mass index); avoidance of foods rich in purines
such as beer, meat especially offal, and shellfish (see table at the back of the booklet);
and a modest intake of alcohol, or abstinence. People need to be aware that diuretic
drugs, commonly used in those with high blood pressure or heart problems, may
worsen their gout and if possible should be avoided, or at least used sparingly.
LOWERING PLASMA URATE CONCENTRATIONS
As the main risk factor for gout is the high level of uric acid in the body fluids,
lowering this to normal levels is a main goal. Although long-term colchicine is used
by many rheumatologists, it does not affect uric acid levels at all - neither production
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nor excretion. For the reasons outlined above, colchicine is best avoided in those with
kidney problems, however.
Medicines which increase the loss of uric acid via the urine (by increasing the FEur)
have been used for more than half a century, in particular probenecid. Unfortunately,
it and other similar medicines become less and less effective as kidney failure
increases in severity, filtration falls and the FEur increases anyway. The exception is
benzbromarone, which we discuss below.
Allopurinol
Remains the mainstay of gout treatment in the long run, as it reduces the production
of uric acid through inhibiting the enzyme that produces it, xanthine oxido-reductase
(XOR). The problem with using allopurinol in people with kidney problems is that it
- and its active product oxipurinol - are both got rid of through the kidney, and both
can accumulate in kidney failure. Whilst not of itself toxic, this seems to place people
at risk for more frequent rashes from the drug. Thus ordinary doses of allopurinol
must be reduced in gout patients with kidney problems. As well, kidney problems
increase the risk of the very rare true allergic reaction to allopurinol, (abbreviated, A)
AHS, which is severe, leads to kidney and liver failure, and can be fatal. Thus
allopurinol is difficult to use in kidney patients, even though it is equally as effective
as in those without kidney problems. However, with dose adjustment appropriate to
kidney function, allopurinol can be used safely for many years. Newer inhibitors are
discussed below.
Given that present treatments, although helpful, are unsatisfactory in many respects,
is there anything new and effective in this area of treatment?
New treatments for recurrent/chronic gout with kidney
problems
Benzbromarone
The first “new” treatment to consider is in fact a 35- year-old one: benzbromarone.
This medicine can reduce the reabsorption of urate, after filtration in the kidney,
through inhibiting the URAT-1 transporter almost completely, with a corresponding
large increase in FEur. It will work even in quite advanced kidney failure to lower
plasma urate concentrations even more effectively than conventional doses of
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allopurinol. Benzbromarone is new to Britain, as it has never been licensed in the UK
and was withdrawn in Europe in 2003. This was because of problems with liver
toxicity, which are however rare - perhaps no more common that the severe reactions
to allopurinol discussed above. Today one can obtain benzbromarone, but only from
abroad on an individual named patient prescription basis, but it is a valuable agent for
treating gout in kidney failure, especially when allopurinol cannot be used, or is
ineffective.
Combinations of benzbromarone with allopurinol have also been investigated and
have now proved to work well. When this idea was first exploited, the doses used
were too small - especially of the benzbromarone - and the combination appeared at
first no more or even less effective than allopurinol alone. Now the double treatment
has been re-examined using higher doses of benzbromarone, and does appear to be
better than allopurinol on its own.
New xanthine oxido-reductase (XOR) inhibitors - Febuxostat
At the moment there about 20 new XOR inhibitors being tested. The renewed
interest in this type of drug, after several decades of inactivity in the area, comes from
the possible need to treat the large number of people with high plasma urate
concentrations, but who do NOT have gout - symptomless hyperuricaemia. This
appears to be an integral part of a syndrome affecting increasing proportions of the
population in developed countries. The clumsily-named “metabolic syndrome”
consists of some or all of: obesity, vascular disease, high blood lipids, resistance to
insulin or actual diabetes - and hyperuricaemia, occasionally gout. As well as the
toxic effects of urate crystals in gout, urate in solution has been proved recently to
have in its own right a powerful toxic action on the lining of blood vessels, and may
be a driver of some aspects of this syndrome. Hence the wish to treat it, even in the
absence of clinical gout.
Febuxostat, the first of these new agents to reach final clinical trials so far, is a non purine antagonist of XOR. It has one great advantage over allopurinol in that it is not
dependent on the kidney at all for its removal from the body - it is got rid of in the
liver. Thus its dosing is simple in kidney failure. Whether it will become a preferable
agent will depend on studies in kidney failure patients with gout. At the moment we
only know it is about as effective as allopurinol in treating long term gout, and that no
major toxicity has so far emerged. But allopurinol has been taken for decades by
some patients, whilst experience of the new drug is only a year or two so far.
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Urate oxidase (rasburicase)
All mammals, other than man and closely related primates, break any urate made in
their bodies down to very a soluble, easily-excreted, non-toxic product called
allantoin:
URATE OXIDASE
Diet and metabolism
uric acid
allantoin
INSOLUBLE
SOLUBLE
The enzyme which does this (and whose activity we lost some 8 million years ago
during our evolution) is urate oxidase, mainly found in the liver in other mammals. It
has been available in semi-purified form in small quantities for some 30 years, but
recently its structure and gene have been elucidated and the pure enzyme is now
readily available, expressed in, and produced from yeast cells in culture. A
preparation of uricase, treated to extend its active life in the bloodstream, is extremely
effective in preventing problems with urate in situations where huge amounts are
released suddenly after tumours are treated - the so-called tumour lysis syndrome.
This tumour lysis syndrome treatment lasts only a few days. However, it has been shown
also that in patients with gout and severe tophi, resistant to other treatments outlined
above, repeated injections of urate oxidase over a year or more can be very effective.
Rather surprisingly, antibodies against the “foreign” (fungal) urate oxidase have not
formed. This type of treatment is only necessary in a very small number of patients.
Losartan and Fenofibrate
Many people with gout also have high blood pressure and high blood
lipids/cholesterol (sometimes as part of the “metabolic syndrome” mentioned above),
and take medicines to treat both of these states as well as gout medicines. In people
with gout, one anti-hypertensive medicine stands out, in that it also lowers plasma
urate levels - the angiotensin-1 (AT1) receptor antagonist losartan. This property is
NOT shared by other similar drugs, and appears unique to this molecule. Similarly of
all the medicines that lower plasma cholesterol concentrations, fenofibrate appears to
have a significant effect in lowering urate levels also. Since many gouty patients also
need medicines for raised lipids and high blood pressure, both of these agents have
specific advantage for them should they need such treatment.
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TREATMENT OF GOUT FOLLOWING TRANSPLANTATION
Finally one particular group of people with reduced kidney function and gout
deserves mention. Gout is very common in patients with organ transplants, being
found in about one quarter of kidney transplant recipients, and more surprisingly
perhaps, in over one half of heart and lung transplant recipients. Often this is not
typical in its presentation, appearing in large joints or even the spine, above the waist,
and often with painless tophi and no arthritis.
Some special features lead to gout in these patients, principally the low filtration rate
of kidney transplant recipients, and particularly some of the medicines used to keep
the grafted organ in place. Here the main offender is cyclosporin, which in a fashion
still unknown reduces urate excretion in the kidney tubules, in addition to lowering
kidney filtration as well. Many patients take diuretics in addition, which can decrease
urate excretion (FEur) even further, as already noted.
All of the above treatment strategies, old and new, are relevant to this special group of
patients. Where possible a transplant recipient with gout, if taking cyclosporin, is
better transferred to an alternative anti - rejection medicine. A particular point for
worry is the interaction of some medicines used to treat rejection, and medicines
given for gout - especially allopurinol. This blocks XOR as noted above, and this
enzyme also leads to the removal of azathioprine, a drug very commonly used until
recently - and still today - to prevent rejection. Thus toxic levels of the active product
of azathioprine, called 6-MP, may accumulate and lead to marrow depression and
even death. The two should therefore not be used together. In contrast, it is safe to use
allopurinol alongside the newer anti-rejection medicine mycophenolate, another
purine enzyme inhibitor (of the enzyme IMP dehydrogenase).
Finally
As always prevention is better than cure: avoiding purines in the diet, losing weight,
avoidance of diuretic medicines where possible, and moderation in alcohol (beer)
intake can all help people with kidney problems avoid gout rather than having to treat
it. To end on a positive note after all these don’ts, cherries have been shown to lower
the plasma urate and should be good in gout.
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Instructions for a Low Purine Diet
Foods and drinks to be avoided, include those illustrated here.
They are listed in detail below.
1.
Food and beverages with a high Purine content - not allowed
1.1
OFFAL - sweetbreads, heart liver, kidney, pate.
1.2
SEAFOOD - Sardines, sprats, herring, fish roe, trout, salmon, lobster, crab
prawns, oysters, cockles, mussels etc.
1.3
VEGETABLES - Asparagus, avocado pears, peas, spinach, mushrooms, broad
beans, cauliflower.
1.4 Soya products, pulses and legumes.
1.5
Alcoholic beverages (beer and yeast extracts. Meat and vegetable extracts
(Marmite, Vegemite, Bovril etc).
2. Food and beverages allowed
2.1
Milk, cheese, eggs, butter, margarine, ice cream
2.2 Bread, flour, cereals
2.3 Sugar, jam, marmalade, honey, sweets
2.4 Salads
2.5 Fresh cooked or tinned fruits, fruit juices
2.6 Puddings
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3. Foods allowed in moderation (one meal per day)
3.1
Beef, lamb, pork, bacon, ham, poultry, sausages, tongue & meat soups
3.2 Carrots, cabbage, courgettes, leeks, brussel sprouts, beans, marrow, courgettes,
potatoes.
3.3 Fish (other than those above in 1)
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Dietary Purine Content of Food
Purine
g/100
Protein
g/100
Meat
Beef liver
Beef kidney
Beef heart
Beef tongue
Beef steak
Calf liver
Sweetbreads
Veal cutlet
Sheep kidney
Lamb chop
Pork liver
Pork cutlet
Bacon
Ham
Sausage (beef)
Sausage (pork)
Rabbit
Venison
0.333
0.285
0.285
0.167
0.151
0.348
1.212
0.152
0.312
0.196
0.289
0.164
0.85
0.136
0.79
0.66
0.118
0.156
19.7
15.4
16.8
16.4
19.5
19
19.6
19.2
16.8
14.9
22
16.4
9.1
19.5
13.8
11.5
20.4
20
Vegetables
Asparagus
Cauliflower
Celery
Kohlrabi
Mushrooms
Peas
Spinach
0.032
0.032
0.020
0.044
0.072
0.072
0.096
2.1
2.4
1.1
2.1
3.5
6.7
2.2
Purine
g/100
Protein
g/100g
0.181
0.372
0.223
0.181
0.177
0.239
20.6
22.1
18
16
16.4
20.1
Fish, seafoods
Anchovies
0.411
Bass
0.073
Bloaters
0.133
Bream
0.072
Cod
0.062
Crab
0.061
Clams
0.136
Eel
0.108
Fish cakes
0.036
Herring
0.378
Kippers
0.091
Lobster
0.100
Lemon Sole 0.054
Mackerel
0.246
Plaice
0.053
Salmon
0.250
Sardines
0.345
Scallops
0.117
Sprats
0.250
Squid
0.135
Trout
0.092
Whitebait
0.335
20
19.5
22.6
19.7
18
19.2
17
18.6
12.1
17
21.2
20
19.9
29
18.1
23
23
22.3
25.1
15
19.2
Poultry
Chicken flesh
Chicken liver
Chicken heart
Duck
Goose
Turkey
26
Dried legumes
Split peas
Red bean
Lentils
Haricot beans
Lima bean
Peanuts
0.195
0.162
0.222
0.230
0.149
0.16
21
20
28
22
21
20
Other
Bovril
Marmite
Oxo cubes
Yeast extracts
0.340
0.356
0.236
2.257
18
2
10
46
Canned
seafoods
Anchovies
Herring
Mackerel
Oysters
Salmon
Sardines
Shrimp
Tuna
26/2/08
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0.321
0.378
0.246
0.116
0.088
0.399
0.231
0.142
Page 25
30
17
26
6
26
24
22
29
Data obtained from: Documenta Geigy Scientific Tables, 5th Edition 1956
The Composition of Foods McCance and Widdowson 1960
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Suggestions for Further Reading
Hyperuricemia and Gout. Becker MA. In:Scriver CR, Beaudet AL, Sly WS, Valle D,
eds. The Metabolic and Molecular Basis of Inherited Disease. New York:McGrawHill, 8th edition:2001: Chapter 106. pp 2513-2535.
Becker MA, Schumacher HR, Wortmann RL et al. Febuxostat compared with
allopurinol in patients with hyperuricemia and gout. New England Journal of
Medicine 2005;353:2450-2461.
Bruce SP. Febuxostat: a selective xanthine oxidase inhibitor for the treatment of
hyperuricemia and gout. Annals of Pharmacotherapy 2006; 40:2187-2194
Cameron JS, Simmonds HA. Uric acid and the kidney. Oxford textbook Clin Nephrol
Eds Davison A, Cameron JS, Grünfeld JP et al. Oxford University Press,2005. (Vol
2)1059 - 1073.
Cameron JS. Uric acid and the kidney. Nucleosides Nucleotides and Nucleic Acids.
2006;25: 1055-1064.
Gibson T, Highton J, Potter C, Simmonds A. Renal impairment and gout. Ann.
Rheum. Dis. 1980;39: 417-423.
Grahame R, Scott JT: Clinical survey of 354 patients with gout. Ann Rheum Dis
29:461-468, 1970.
Grahame R, Simmonds A, Carrey E, Gout - the ‘at your fingertips’ guide. Booklet,
published by Class, London: 2003.
Jordan KM, Cameron JS, Snaith M et al. British Society for Rheumatology and British
Health Professionals in Rheumatology guideline for the management of gout.
Rheumatology 2007;46: 1372-1374.
Marinaki AM, Cameron JS, Simmonds HA. Inherited disorders of purine metabolism
and transport. Oxford textbook of clinical nephrology 3rd edition. Eds Davison A,
Cameron JS, Grunfeld JP et al. Oxford University Press, Oxford, 2005. (Vol 3) pp
2381-2395.
Perez Ruiz F, Calabozo M, Fernandex-Lopez J et al. Treatment of chronic gout in
patients with renal function impairment. An open randomized actively controlled
study. J Clin Rheumatol. 1999; 5: 49-55.
28
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Page 27
Terkeltaub R, Bushinsky DA, Becker MA. Recent developments in our understanding
of the renal basis of hyperuricemia and the development of novel antihyperuricemic
drugs. Arthritis Research and Therapy 2006; 8 [suppl 1] S4
UK Gout Society.org Information about the causes and treatment of gout. Links to
organisations that are committed to education, health promotion and the prevention
of gout.
- The above articles in turn contain details of a large number of other papers and
chapters in books on the subject of gout.
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Contact Addresses for Further Help
Information and PUMPA patient support:
Mrs Joan Martin, Patient Support Group, PUMPA tel: 01293 851877
Laboratory diagnosis
Dr Lynette Fairbanks, Dr Tony Marinaki, Purine Research Laboratory, 3rd Floor,
Block 7, South Wing, St Thomas’ Hospital, London SE1 7EH
tel: 0207 188 1266, fax: 0207 188 1280.
E-mail: lynette.fairbanks@kcl.ac.uk tony.marinaki@kcl.ac.uk
Genetic Counselling
Genetic counselling, if required, is available at your nearest Regional Hospital, to
which you may be referred by your GP.
For information about gout or kidney failure
GOUT: Answers at your fingertips. R Grahame, H A Simmonds, E Carrey.
(Class Publishing London Ltd, 2007. ISBN 978 1 85959 067 6)
UK GOUT SOCIETY http://www.ukgoutsociety.org/index.htm
info@ukgoutsociety.org
KIDNEY RESEARCH UK, King’s Chambers, Priestgate, Peteborough, PE1 1FG
www.nkrf.org
British Kidney Patients Association (BKPA), Bordon Hants, GU35 9JZ
All about gout.doc. A Patients Guide to Managing Gout
The publication of the information in the above booklet has been sponsored by an
unrestricted educational grant from Merck Sharp & Dohme Limited
30
Notes
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Notes
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Notes
33
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Notes
34
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ADA Deficiency Book - A5

Transcription

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