Gout and Hyperuricemia

in Chronic Kidney Disease

WHAT IS CLINICALLY SIGNIFICANT?

Background
Pathogenic Relationships
Kidney Manifestations
Role of Lowering Serum Uric Acid
Conclusion

BACKGROUND

ETIOLOGIES OF
HYPERURICEMIA AND GOUT

In chronic kidney disease (CKD), gout is a concomitant

illness that increases health risk and treatment burden.
The direct clinical impact of gout is also amplified by the
comorbidities it shares with CKD hypertension, diabetes, and features of the metabolic syndrome. Ironically,
CKD may often lead to gout, as observational studies have
found CKD to be the third most common independent
risk factor for gout after obesity and hypertension.1,2 CKD
is associated with decreased excretion of uric acid and
resultant hyperuricemia, a major risk factor for gout. Other
mechanisms may be implicated in CKD since variations
in serum uric acid do not account for most of the risk for
developing gout.1,3

Because humans lack uricase, they cannot convert

the uric acid generated during purine metabolism
into a soluble form. This can lead to an increased risk
for hyperuricemia and monosodium uric acid crystallization in joints and tissues, a hallmark of gout.
Hyperuricemia can be caused by the overproduction
of uric acid, but is more often the result of insufficient
kidney uric acid excretion. Because a family history is
often seen in primary gout, much research is focused
on genes that cause hyperuricemia, notably those
that regulate renal uric acid transport, such as human
urate transporter 1 (URAT1).11 Genetic polymorphisms
in anion transporters such as URAT-1 and SLC2A9,
which encodes for GLUT9, can cause hyperuricemia
by decreasing proximal tubular uric acid clearance.12-14
Other non-modifiable risk factors for gout include
male gender, increasing age, and menopause.11,15

Conversely, there is evidence that gout and associated

hyperuricemia may independently impair kidney function.4,5
Hyperuricemia in the presence of gout, as well as the use
of gout medications that are potentially harmful to the kidneys, are initiation factors for developing CKD, and progression factors for worsening CKD.6

Approximately 15% of uric acid clearance occurs via

the gastrointestinal tract, and therefore small bowel
disease can contribute to increased serum uric acid.16
A variety of medications can increase serum uric acid,
including loop and thiazide diuretics. High intake of
meat, shellfish, alcohol, and fructose also can cause
hyperuricemia,17,18 while obesity increases the risk for
its development by three-fold.19 For many people,
these causes of hyperuricemia will not lead to gout,
but for those who are susceptible, these factors may
trigger gout attacks.18

Observational data also suggest that hyperuricemia, even

in the absence of gout, may independently worsen CKD,7,8
possibly via a pathogenic role in hypertension (Figure 1),
and diabetic nephropathy, the two leading causes of CKD.9,10
This bulletin highlights the clinical significance of both gout
and hyperuricemia by discussing their etiologies, epidemiology, and relationship to CKD.

Uric acid and chronic renal disease

47

EPIDEMIOLOGY AND
PATHOGENIC RELATIONSHIPS
GOUT AND CKD
Gout has been steadily increasing worldwide, and is
now the most common type of inflammatory arthropathy.11 In the United States alone, its prevalence
more than doubled between the 1960s and the
1990s,20,21 and it is now estimated at 3.9% of U.S. adults
(8.3 million adults 6.1 million men and 2.2 million
women).20,22 Hyperuricemia is also common, with a
prevalence of 6-8% in healthy adults, and a prevalence
of 1 in 3 adults who have uncontrolled hypertension
and several cardiovascular risk factors.23 Concomitantly, the prevalence of CKD has been increasing, with
estimates at 14% of adults in the United States,24 and
8-16% globally.25 The parallel rise in gout and CKD
(Figure 2) has led to investigations to study their relationship, including a retrospective cohort study based
on 54 years of follow-up data from the Framingham
Heart Study, which found that the risk of developing gout in CKD doubled compared to subjects not
having CKD and gout at baseline (HR=2.09; 95% CI
1.41 to 3.08). This difference remained significant after
adjusting for other known gout risk factors.1,26

Figure 1. The potential interrelationships of uric acid,

xanthine oxidase activity, and clinical endpoints of
cardiovascular and renal disease
Adapted from: Kang DH, Nakagawa T. Uric acid and chronic
renal disease: possible implication of hyperuricemia on
progression of renal disease. Semin Nephrol 2005;25:43-9.

In this prospective study based on 54 years of follow-up

data from FHS participants, the risk of gout associated
with CKD was doubled (HR=2.09; 95% CI 1.41 to 3.08)
in participants free from CKD and gout at baseline.
CLINICAL COMMENTARY www.jasn.org
These associations persisted in both sexes, as well as in
our additional analyses including those with CKD at
and compon
Chronic independent
kidney
baseline, and were
of
other knowndrome.
riskThis
Uric acid
disease
factors of gout, including age, BMI, alcohol ciations
use, tha
ments
by ro
smoking, hypertension and diabetes.
Overall,
these
Uric acid
does suppo
PATHOGENICALLY
ndings provide Underlying
prospective evidence that individuals
RELATED
pathogenic r
condition
Chronic kidney
with CKD are at an increased future
risk of gout indeDose-resp
disease
pendent of other known risk factors. Our sensitivitytoanaestablish,
Chronic kidney extremedose
lyses indicated that
even after
andthe u
Uric acid
* assuming
disease
the study by
unlikely degrees of misclassication and bias, the relative
was constru
risk estimate is about 1.8, suggesting that the truedata
relathat disp
ship
between
tive risk might be Uric
stronger.
acid
UNRELATED
a continu
Historically, the impact of CKD
on gout has asbeen
COEXISTENCE
Chronic kidney
finding is on
1 25 26
as different studiesdisease
observed different
debated,
current data
results. One factor that was often involved in the debates
more than it
Figure 1. Possible relationships between hyperuricemia and chronic kidney disease.
tions balanc
is
SUA.
However,
not
all
patients
with
hyperuricaemia
Asterisk indicates true causality.
Figure 1 Kaplan-Meier failure estimates for incident chronic
this
27 discussio
28
develop gout, and the reasons remain unclear.tion
kidney
diseaseKaplan-Meier
(CKD) to incident
amongfor
participants
as prop
Figure 3. Possible relationships between hyperuricemia
Figure2.
failuregout
estimates
incident
Furthermore,
is difcult to ascertain if hyperuricaemia
and need no
foremost
importance
is itwhether
who chronic
developed
incident
CKD
aftertothe
baseline
visit
and thoseOf and
chronic
kidney
disease endowed with uricase and evolved with
kidney
disease
(CKD)
incident
gout
among
25
uricemia
there
is
a
biologic
basis
for
this
entity.
extremely
low
plasma
and
tissue
levels
of
To
test ca
preceded
CKD
or
whether
the
reverse
is
true.
who participants
never developed
CKD
in
the
original
Framingham
Heart
who developed incident CKD after the
Adapted
from: data
Moeshows
OW. inPosing
question
again:
does se- quences, and
histopathologic
uricthe
acid,
which
are
then rendered
Study
cohort.visit and those who never developed CKD in Humanchronic
the uric
inuence
of
SUA
with
the
relationship
between
baseline
acid nephropathy exist? J Am Soc Nephrol

Comparisons have been made between unadjusted and

SUA adjusted ORs as well as multivariable ORs with or

terstitial inflammation and fibrosis coex- verely hyperuricemic experimentally. result from
2010;
21:395-397.
isting with
crystalline
uric acid deposits, Similar findings in higher primates with conjunction
Adapted from: Wang W, Bhole VM, Krishnan E. Chronic
which areWang
interpreted
by
smokrelative highdoi:10.1136/bmjopen-2014-006843
normal plasma uric acid sitions. Tem
W, et al. some
BMJ as
Open
2015;5:e006843.
*True causality
kidney disease as a risk factor for incident gout among mening guns.6 A scatter of physiology stud- levels would be substantially more per- ful and rev
and women: retrospective cohort study using data from ies also showed abnormal indices of renal suasive. The current status of the bench data. The oc
the Framingham Heart Study. BMJ Open. 2015;5:e006843. and endothelial function in the backdrop data is convincing for the rodent model fore the dise
of asymptomatic hyperuricemia. None but still uncertain for humans. For hu- to a causal r
of these provide proof and most of them mans, one needs to turn to clinical data larly impor
GFR begets h
are challenged by studies showing con- that are more challenging to unravel.
trary results. The most convincing data
Because one is equipped almost ex- cites little de
to date are derived from rodent models. clusively with epidemiologic data in hu- et al. showe
Heinig and Johnson7 eloquently summa- mans, one can apply some of Hills cedes reduct
rized this body of literature recently. In- guidelines to attempt to gain more in- The amelior
duction of hyperuricemia elevates BP sight into causality. The strength of asso- nation or red
HYPERURICEMIA AND CKD
and produces renal microvascular, glo- ciation is variable from study to study strongly sup
Epidemiologic studies have also addressed the associationmerular, and tubulointerstitial lesions ranging from none to weak8 10; space nately, we do
of hyperuricemia and prevalent or worsening CKD. The
that are without doubt detrimental to the does not permit exhaustive citation of all data. Althou
URIC
NEPHROLITHIASIS
largest study included 177,570 patients in the US Renal Dataorganism.
The ACID
mechanisms
by which studies. A recent article in this journal emerged in
transpire
are
not
yet
known
strongest
System (USRDS) database followed over 25 years. Subjectsthese lesions
Although gout patients
have aprovided
higherone
riskoffortheuric
acid associa- ling, definiti
theseformation
models in hand.
Based
on without
tions to date.
Obermayr
et al.11 prospec- ing a causativ
within the highest quartile of serum uric acid had a hazard even with
stone
than
people
gout,
the primary
database,
one will have
to promotes
tively followed
more lithiasis
than 21,000
ratio of 2.14 for CKD, a level of risk that ranked third after the rodent
metabolic
abnormality
that
uric acid
is pa- ease is still n
the compelling view espoused tients for a median of 7 yr with different these years. W
proteinuria and severe obesity.27 However, causality cannotagree with
excessive urinary acidity, since urine pH is the major deterand Johnson that the data are serum uric acid levels but the same base- general poin
be established solely from observational studies, especiallyby Henin
minant of uric acid crystallization.28 Acidic urine is present
For the r
very close to satisfying Kochs criteria for line estimated GFR. They found mild hybecause the temporal relationship between the onset of
in people with gout, even in the
absence(7.0
of kidney
stones,
uric acid nephropathy.
peruricemia
to 8.9 mg/dl) nearly ning of this c
29
CKD and hyperuricemia is unclear. Accordingly, serum uric
but is worse inthe
stone
formers,
and this
is associated
with dis- driving one
In contradistinction,
human
evi- doubled
the risk
for incident kidney
30
acid levels have not always been found to be an indedecreased
ammonium
excretion.
Although
hyperuricosdence supporting a biologic mechanism ease, and more severe hyperuricemia continue un
pendent risk factor for CKD progression, especially when of uric uria
is an important
factor
uric tripled
acid stones
acidinduced
injury in the
kidneyin causing
(9.0 mg/dl)
the risk.inThe sig- negative ans
28
baseline kidney damage is considered.
some
groups,
this
the case
for most
people
is rather
weak patient
in comparison
to the
ro-is not
nificant
odds ratios
survived
albeit di- uric acid per
29
with
uric
acid
nephrolithiasis.
Likewise,
the
association
dent
data.
One
needs
to
exercise
heightminished
with
adjustments
for baseline disease in hu
Observational studies and animal models suggest that
between
uric acid data
nephrolithiasis
and GFR,
the metabolic
to extrapolate
gath- estimated
gender, age,syndrugs po- The impact,
hyperuricemia itself is directly nephrotoxic, even before theened caution
species
as rodents
altering serumbut
uric rather
acid levels, the same ma
drome
is notsuch
so much
relatedtentially
to hyperuricemia,
clinical syndrome of gout develops, and may be a mecha- ered from

the original Framingham Heart Study cohort.

KIDNEY MANIFESTATIONS
OF GOUT

nism in the pathogenesis of hypertension, cardiovascular

disease, and CKD. But studies are conflicting and estab- 396
lishing how hyperuricemia, hypertension, and CKD are
connected is difficult because of 1) the direct effect kidney
function itself has on uric acid levels, and 2) the association
of hyperuricemia with other causes of CKD, notably hypertension, confounding the interpretation of direction or
mechanism of the association.28 The possible pathogenic
relationships between hyperuricemia and CKD are represented in Figure 3.

to excessive urinary acidity. Urinary pH and ammonium

excretion
directly
correlated
with the number of metaJournal of are
the American
Society
of Nephrology
bolic syndrome features, with a greater urinary acidity and
lower ammonium excretion correlated to more features. In
fact, clinical studies have demonstrated that insulin resistance is associated with excessive urinary acidity.28,31

JA

KIDNEY MANIFESTATIONS OF
HYPERURICEMIA

LOWERING SERUM URIC ACID TO

TREAT GOUT IN THE SETTING OF CKD

URATE NEPHROPATHY

The 2012 American College of Rheumatology (ACR)

Guidelines emphasizes both non-pharmacologic and pharUrate nephropathy is defined as urate crystal deposition
macologic approaches for managing gout and lowering
in the physiologic pH of the renal medulla, rather than the
serum uric acid levels. The recommended serum uric acid
tubular lumen obstruction caused by uric acid lithiasis in
level should be low enough to effectively improve and
tumor lysis syndrome or uricase knockout mice. Pathologmaintain the signs and symptoms of gout, a goal most
ical features observed in the kidneys of gout patients are
often associated with a level of <6 mg/dL. The two first-line
those mainly associated with hypertensive kidney disease:
options for urate lowering therapy (ULT) are the xanthine
advanced arteriosclerosis, glomerulosclerosis, and interoxidase inhibitors, febuxostat and allopurinol. Febuxostat
stitial fibrosis. (Figure 4) Urate crystal deposition is present,
does not require renal dose adjustment in mild to moderate
but the focal nature of that feature appears inconsistent
CKD. Because insufficient evidence exists on its safety in
with the diffuse nature of the kidney disease.32 And possibly
CKD stage 4 or worse (eGFR of 30-89 mL/min/1.73 m2), no
analogous to the fact that most people with hyperuricemia
recommendation was issued for febuxostat in this setting.
do not develop gout, 86% of postmortem cases with renal
In CKD, the starting dose for allopurinol should not be more
28,33
medullary urate deposits had not developed gout in life.
than 100 mg/day in moderate to severe CKD, followed by
111
Chapter 9 ClinicalFeaturesofGout
gradual upward titration of the maintenance dose, which
can exceed 300 mg/day. Anti-inflammatory prophylaxis of
acute gouty arthritis also involves the continuation of established pharmacologic ULT, without interruption, during
an acute gout attack.17
The ACR recommends prophylaxis when initiating ULT because the rapid decrease in serum urate can often trigger
gout flares. First line options include low-dose colchicine
(0.6 mg orally once or twice daily, with lower doses for
moderate-to-severe CKD (eGFR of 15-59 mL/min/1.73 m2)
and potential drug-drug interactions). Although low-dose
non-steroidal anti-inflammatory drugs (NSAIDs) such as
naproxen, 250 mg orally twice daily is recommended by
the ACR. NSAIDs should generally be avoided in CKD. A
stronger level of evidence exists for using colchicine.34
Figure9-10
4 Urate nephropathy. There is chronic tubulointerstitial nephriFigure
tis. Note the tubule distended by a collection of needle-like spaces, originally containing urate deposits, associated with multinucleated giant cells
(PAS stain, magnification 40). ( 2011 American College of Rheumatology.
Available online at Rheumatology Image Bank: http://images.rheumatology
.org/viewphoto.php?albumId=75676&;imageId=2862276.)

LOWERING SERUM URIC ACID

nah, Georgia, USA.
reserved. Available
at http://library.med.utah.edu/
TOAll rights
TREAT
CKD

Figure 9-11 This is chronic urate nephropathy with pale yellowish tan
tophaceous deposits in the medulla. (Image Edward C. Klatt, MD, SavanWebPath/RENAHTML/RENAL121.html.)

In view of the pathogenic connection between CKD and

cases, this is idiopathic. Acidic urine is observed in people

hyperuricemia, researchers have been evaluating how
with gout,
in the
absence of renal stones, but is worse in
With specific
respect
to uric
urate acid
nephropathy
(gouty
Figure
4. even
Urate
nephropathy
lowering
serum
levels might
reduce the progres52
stone formers, and this is associated with a deficit of ammonephropathy), Sydenham9 describes morbific matter in
Adapted
from:
Taylor
WJ,
Grainger
R.
In:
Terkeltaub
R,
ed.
sion
of
CKD.
Data
is
based
mostly
on
observational studnium excretion.55
what may be an early account of gouty nephopathy:
Gout
and Other
Crystal Arthropathies:
1st ed.
Philadelphia,
ies and small clinical trials,35-37 and a significant problem
Although
hyperuricosuria
is a very important
factor
in
The viscera in time are so much injured, from the stagnaleading
to uric
acid stones2012:105-120.
in some patient groups, this is
PA:
Elsevier
Saunders;
comparing
their
data,
asideoffrom
tion of thewith
morbific
matter therein,
that
the organs
secre-methodology and
not present in most people with uric acid nephrolithiasis.
confounding
disease
states
and
is the lack of
tion no longer
perform their
functions,
whence
thetreatments,
blood,
Hyperuricosuria may occur in rare metabolic conditions
overcharged
with vitiated
humours,hyperuricemia.
stagnates, and theLevy, et al conducted
uniformity
in defining
such as Lesch-Nyhan
syndrome, Kelley-Seegmiller syndrome,
OTHER
DISEASES
gouty matter
ceasesretrospective
to be thrown upon
the extremities
a large
review
of 111,992aspatients defined as
some glycogen storage diseases, or rare cases of URAT1
formerly, so
that at hyperuricemia
length death frees him
hisof
misery.
56 or GLUT9 (SLC2A9)57 mutations associated
having
at afrom
level
> 7 mg/dL, and found
(SLC22A12)
Less
common
kidney manifestations of hyperuricemia inwith
severe
hypouricemia
(see
Chapter
4).
In
the
middle
of
the
20th
century,
it
was
well
recognized
that patients treated with uric acid lowering therapy (one
clude: familial juvenile hyperuricemic nephropathy (FJHN),
Recently, an association between the metabolic synthat patientsof
with
could frequently
developfebuxostat,
renal impair-or probenecid),
thegout
following:
allopurinol,
an autosomal dominant disease leading to end-stage renal 59
drome and uric acid nephrolithiasis has been identified.
ment. In that era prior to the widespread introduction of
who
achieved
a
serum
uric
acid
< therapy,
6 mg/dL, showed a 37%
disease
(ESRD)appears
at an early
reduced
fractional
This association
not toage,
be due
to the known
asso-excretion
effective urate-lowering therapy or antihypertensive
38
reduction
in
outcome
events.
In
a
recent
of
uric
acid,
renal
interstitial
uric
acid
deposits,
and
sporadciation of hyperuricemia and the metabolic syndrome but
renal failure in patients with primary gout was not rare.
For small prospecrandomized,
open-label
rather
an arthritis;
associationcomplete
between anorunduly
urinary pH
example, a tive,
case series
of approximately
300 study
patientswith
with21 patients receivic
gouty
partialacidic
hypoxanthine-guanine
and the metabolic syndrome. The
principal
mechanisms
of
mainly untreated
gout from the
observed conventional
significant
ing febuxostat
and1950s
19 receiving
treatment, the
phosphoribosyltransferase
(HPRT)
deficiency
(Lesch-Nyhan
urinary acidity in uric acid nephrolithiasis are increased net
renal diseaseauthors
in 18% reported
to 25% of renoprotective
cases, and renal histologic
effects
from
febuxostat in
and
syndromes,
respectively);
acute changes,
uric
acid Kelley-Seegmiller
excretion and impaired
buffering caused
by inadequate
in 1960, were observed in the large majority39of peohyperuricemic
patients
with
CKD.
59
acid-related
nephropathy,
a
condition
that
is
not
usually
ammonium excretion. Urinary pH and ammonium excreple with gout. However, whether these observations were
associated
withcorrelated
gout, butwith
with
tion are directly
thea sudden,
number ofmassive
metabolicuric acid
due to hyperuricemia
directly
or topost
hypertension
that is often
At a single
center,
hoc analysis
of 113 patients who had
syndrome
features,
with more features being associated
with 28 coexistent with gout is difficult to determine. Pathologically,
load
caused
by chemotherapy-induced
tumor lysis.
completed a 2-year, single-blind, randomized controlled
a more acidic urine and lower ammonium excretion. In studthe kidneys of people with gout are characterized mainly by
trial of
allopurinol
patientsrenal
received
ies using the hyperinsulinemic euglycemic clamp technique,
changes typically
associated
with (56
hypertensive
disease:allopurinol and 57
were in the control
group), showed
improved estimated
insulin resistance was shown to be associated with excessive
advanced arteriosclerosis,
glomerulosclerosis,
and interstiurinary acidity.58
tial fibrosis (Figs.
9-10 andfiltration
9-11). Urate
depositioncardiovascular
is
glomerular
ratecrystal
and reduced
risk.40
observed, but the focal nature of that feature seems inconsistent with the diffuse nature of the renal disease.60 FurtherUrate Nephropathy
more, perhaps
analogous to the fact that most people with
4
The extent to which hyperuricemia causes rather than is
hyperuricemia do not develop gout, 86% of postmortem cases

The larger Preventing Early Renal Function Loss (PERL)

Allopurinol study, an international, multi-center, stratified,
double-blind, placebo-controlled, parallel-group randomized clinical trial, is currently investigating the effect of
allopurinol in delaying the progression of CKD in type 1
diabetes. The reason for creating this trial stems from
growing evidence that hyperuricemia may have a role in
the pathogenesis of diabetic nephropathy and the progression of CKD observed in type 1 diabetes. This evidence
includes epidemiologic data,41 and prospective data from
trials such as Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist
Losartan (RENAAL), in which lowering serum uric acid
through the use of losartan accounted for 20% of the renoprotection provided by this drug.41,42 Mounting evidence
over the last decade provides increasing support for the
hypothesis that hyperuricemia leads to vasoconstriction
and vascular remodeling that results in hypertension and
contributes to the progression of CKD in at risk individuals.10

DISCLAIMER
Information contained in this National
Kidney Foundation educational resource
is based upon current data available
at the time of publication. Information
is intended to help clinicians become
aware of new scientific findings and
developments. This clinical bulletin is not
intended to set out a preferred standard
of care and should not be construed as
one. Neither should the information be
interpreted as prescribing an exclusive
course of management.

CONCLUSION
Gout and hyperuricemia are clinically significant in the
setting of CKD, especially when drugs used for their
management can further impair kidney function. The
established role of CKD as an independent risk factor
for gout may therefore warrant screening for CKD when
gout is first diagnosed.23 The role of hyperuricemia as an
independent risk factor for CKD, however, is still being
debated. Large randomized controlled trials can provide
definitive answers about its relationship to CKD, and how its
treatment might forestall CKD progression in populations
such as those with hypertension and diabetic nephropathy.
Until the completion of large randomized controlled
trials that support safety and efficacy, the ACR does
not recommend serum uric acid lowering therapy
for asymptomatic hyperuricemia.17 The dangers of
inappropriately treating asymptomatic hyperuricemia are
well documented,43-45 especially in the elderly.41
As emphasized by both the ACR and the National Kidney
Foundation, lifestyle and dietary modifications that
ameliorate the features of gout and hyperuricemia, along
with appropriate pharmacologic treatments for gout and
uric acid nephrolithiasis, are the proven strategies for
reducing the risk of developing or worsening CKD.17,46

1. Krishnan E. Chronic kidney disease and risk of incident gout among middle-aged men:
a seven-year prospective observational study. Arthritis Rheum. 2013;65:3271-3278.

25. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and
perspectives. Global kidney disease 3. Available at: www.thelancet.com. Published
online May 31, 2013. http://dx.doi.org/10.1016/50140-6736(13)60687-X.

2. Juraschek SP, Kovell LC, Miller ER, et al. Association of kidney disease with
prevalent gout in the United States in 1988-1994 and 2007-2010. Semin Arthritis
Rheum. 2013;42:551-561.

26. Wang W, Bhole VM, Krishnan E. Chronic kidney disease as a risk factor for incident
gout among men and women: retrospective cohort study using data from the
Framingham Heart Study. BMJ Open. 2015;5:e006843.

3. Roddy E, Choi HK. Epidemiology of gout. Rhem Dis Clin N Am. 2014;40:155-175.

27. Hsu CY, Iribarren C, McCulloch CE, et al. Risk factors for end-stage renal disease:
25-year follow-up. Arch Intern Med. 2009;169:342-350.

4. Jing J, Kielstein JT, Schultheiss UT, et al. Prevalence and correlates of gout in
a large cohort of patients with chronic kidney disease. Nephrol Dial Transplant.
2015;30:613-621.

28. Taylor WJ, Grainger R. In: Terkeltaub R, ed. Gout and Other Crystal Arthropathies:
1st ed. Philadelphia, PA: Elsevier Saunders; 2012:105-120.

5. Y
 u KH, Kuo CF, Luo SF, et al. Risk of end-stage renal disease associated with gout:
a nationwide population study. Arthritis Res Ther. 2012;14:R83.

29. Cameron MA, Sakhaee K. Uric acid nephrolithiasis. Urol Clin North Am.
2007;34:335-346.

6. Badve SV, Brown F, Hawley CM, et al. Challenges of conducting a trial of

uric-acid-lowering therapy in CKD. Nat Rev Nephrol. 2011;7:295-300.

30. Gibson T, Highton J, Potter C, et al. Renal impairment and gout. Ann Rheum Dis.
1980;39:417-423.

7. Obermayr RP, Temmi C, Gutjahr G, et al. Elevated uric acid increases the risk for
kidney disease. J Am Soc Nephrol. 2008;19:2407-2413.

31. Sakhaee K, Maalouf NM. Metabolic syndrome and uric acid nephrolithiasis.
Semin Nephrol. 2008;28:174-180.

8. Feig DI. Uric acid: a novel mediator and marker of risk in chronic kidney disease?
Curr Opin Nephrol Hypertens. 2009;18:526-530.

32. Feig DI, Kang D, Johenson RJ. Uric acid and cardiovascular risk. N Engl J Med.
2009;359:1811-1821.

9. B
 ellomo G. Uric acid and chronic kidney disease: a time to act? World J Nephrol.
2013;2:17-25.

33. Linnane JW, Burry AF, Emmerson BT. Urate deposits in the renal medulla.
Nephron. 1981;29:216-222.

10. F
 eig DI. Serum uric acid and the risk of hypertension and chronic kidney disease.
Curr Opin Rheumatol. 2014;26:176-185.

34. Khanna D, Khanna PP, Fitzgerald JD. 2012 American College of Rheumatology
Guidelines for Management of Gout. Part 2: Therapy and Antiinflammatory
Prophylaxis of Acute Gouty Arthritis. Arthritis Care Res. 2012; 64:1447-1461.

11. Roddy E, Doherty M. Epidemiology of gout. Arthritis Res Ther. 2010;12:223.

12. G
 raessler J, Graessler A, Nuger S, et al. Association of the human urate
transporter 1 with reduced renal uric acid excretion and hyperuricemia in a
German Caucasian population. Arthritis Rheum. 2006;54:292-300.

35. Fairbanks LD, Cameron JS, Venkat-Raman G, et al. Early treatment with allopurinol
in familial juvenile hyperuricaemic nephropathy (FJHN) ameliorates the long-term
progression of renal disease. QJM. 2002;95:597-607.

13. M
 cArdle PF, Parsa A, Chang YP, et al. Association of a common nonsynonymous
variant in GLUT9 with serum uric acid levels in old order Amish. Arthritis Rheum.
2008;58:2874-2881.

36. Siu YP, Leung KT, Tong MK, et al. The use of allopurinol in slowing the progression
of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis.
2006;47:51-59.

14. P
 arsa A, Brown E, Weir MR, et al. Genotype-based changes in serum uric acid
affect blood pressure. Kidney Int. 2012;81:502-507.

37. Kanbay M, Ozkara A, Selcoki Y, et al. Effect of treatment of hyperuricemia with

allopurinol on blood pressure, creatinine clearance, and proteinuria in patients
with normal renal functions. Int Urol Nephrol. 2007;39:1227-1233.

15. H
 ak AE, Curhan GC, Rodstein F, et al. Menopause, post-menopausal hormone use,
and risk of incident gout. Ann Rheum Dis. 2010;69:1305-1309.

38. Levy GD, Rashid N, Niu F, et al. Effect of Urate-lowering therapies on renal disease
progression in patients with hyperuricemia. J Rheumatol. 2014;41:955-962.

16. C
 annella AC, Mikuls TR. Understanding treatments for gout. Am J Manag Care.
2005;11:S451-S458.

39. Tanaka K, Nakayama M, Kanno M, et al. Renoprotective effects of febuxostat in

hyperuricemic patients with chronic kidney disease: a parallel-group, randomized,
controlled trial. Clin Exp Nephrol. Published online: 13 February 2015.

17. K
 hanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology
guidelines for management of gout. Part 1: systematic nonpharmacologic and
pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res.
2012;64:1431-1446.

40. Goicoechea M, Garcia de Vinuesa S, Verdalles U, et al. Allopurinol and

progression of CKD and cardiovascular events: long-terms follow-up of a
randomized clinical trial. Am J Kidney Dis. 2015;65:543-549.

18. Choi HK. A prescription for lifestyle change in patients with hyperuricemia and
gout. Curr Opin Rheum. 2010;22:165-172.

41. Maahs DM, Caramori ML, Cherney DZI, et al. Uric acid lowering to prevent
kidney function loss in diabetes: the preventing early renal function loss (PERL)
allopurinol study. Curr Diab Rep. 2013;13:550-559.

19. H
 wang LC, Tsai CH, Chen TH. Overweight and obesity-related metabolic disorders
in hospital employees. J Formos Med Assoc. 2006;105:56-63.
20. Z
 hu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US
general population: the National Health and Nutrition Examination Survey
2007-2008. Arthritis Rheum. 2011;63:3136-3141.

42. Miao Y, Ottenbros SA, Laverman GD, et al. Effect of a reduction in uric acid on
renal outcomes during losartan treatment: a post hoc analysis of the reduction
of endpoints in non-insulin-dependent diabetes mellitus with the Angiotensin II
Antagonist Losartan Trial. Hypertension. 2011;58:2-7.

21. Lawrence RC, Felson DT, Helmick CG, et al. The National Arthritis Data Workgroup.
Estimates of the prevalence of arthritis and other rheumatic conditions in the
United States: part II. Arthritis Rheum. 2008;58:26-35.

43. Carnovale C, Venegoni M, Clementi E. Allopurinol overuse in asymptomatic

hyperuricemia: a teachable moment. JAMA Internal Medicine. July 2014;174:10311032.

22. Centers for Disease Control and Prevention (CDC). National Center for Health
Statistics (NCHS). National Health and Nutrition Examination Survey Questionnaire
(NHANES) 2007-2008. Hyattsville, MD: U.S. Department of Health and Human
Services, Centers for Disease Control and Prevention; 2009. Available at: http://
wwwn.cdc.gov/nchs/nhanes/search/nhanes07_08.aspx. Accessed May 10, 2014.

44. Kang Y, Kim MJ, Jang HN, et al. Rhabdomyolysis associated with initiation of
febuxostat therapy for hyperuricaemia in a patient with chronic kidney disease.
J Clin Pharm Therapeutics. 2014;39:328-330.
45. P
 asina L, Brucato AL, Djade CD. Inappropriate prescription of allopurinol and
febuxostat and risk of adverse events in the elderly: results from the REPOSI
registry. Eur J Clin Pharmacol. 2014;70:1495-1503.

23. Juraschek SP, Kovell LC, Miller ER, et al. Dose-response association of uncontrolled
blood pressure and cardiovascular disease risk factors with hyperuricmemia and
gout. PLoS ONE; 2013. 8:Article ID e56546.

46. A Clinical Update on Gout: Optimizing Care for Patients with Chronic Kidney
Disease. 2014, National Kidney Foundation, Inc. www.kidney.org/professionals.

24. U
 .S. Renal Data System (USRDS). USRDS 2013 Annual Data Report: Atlas of Chronic
Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD:
National Institutes of Health, National Institute of Diabetes and Digestive and
Kidney Diseases; 2013.

Sponsored by

Takeda Pharmaceuticals, USA

Takeda did not contribute to the development
of the content for this resource.
The content does not necessarily reflect the views,
opinions, or commercial interests of Takeda.

30 East 33rd Street

New York, NY 10016
800.622.9010
www.kidney.org
6

2015 National Kidney Foundation, Inc. 02-10-6972_CBF