Gout and Hyperuricemia

in Chronic Kidney Disease

WHAT IS CLINICALLY SIGNIFICANT?

Background
Pathogenic Relationships
Kidney Manifestations
Role of Lowering Serum Uric Acid
Conclusion
 BACKGROUND
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, diabe-
tes, 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
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 kid-
neys, are initiation factors for developing CKD, and progres-
sion factors for worsening CKD.6
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, epidemiol-
ogy, and relationship to CKD.
Uric acid and chronic renal disease
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.
ETIOLOGIES OF
HYPERURICEMIA AND GOUT
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 crys-
tallization 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
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
47
EPIDEMIOLOGY AND
PATHOGENIC RELATIONSHIPS
GOUT AND CKD
Gout has been steadily increasing worldwide, and is
now the most common type of inflammatory arthro-
pathy.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 Concomitant-
ly, 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 rela-
tionship, including a retrospective cohort study based
on 54 years of follow-up data from the Framingham
Heart Study, which found that the risk of develop-
ing 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
2
Comparisons have been made between unadjusted and In this prospective study based on 54 years of follow-up
SUA adjusted ORs as well as multivariable ORs with or 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
baseline, and were Chronic independent
kidney of other knowndrome.
Uric acid riskThis
disease
factors of gout, including age, BMI, alcohol ciations use, tha
smoking, hypertension and diabetes. Uric acid Overall, these
ments by ro
PATHOGENICALLY
ndings provide Underlying prospective evidence that individuals does suppo
RELATED condition pathogenic r
with CKD are at an increased future risk of gout inde-
Chronic kidney
Dose-resp
disease
pendent of other known risk factors. Our sensitivitytoana- establish,
lyses indicated that even after
Uric acid * assuming
Chronic kidney extremedose andthe u
disease the study by
unlikely degrees of misclassication and bias, the relative was constru
risk estimate is about 1.8, suggesting that the truedata rela-
that disp
tive risk might be Uric stronger.
acid
ship between
UNRELATED
Historically, the impact of CKD
COEXISTENCE
on gout has asbeen
Chronic kidney
a continu
1 25 26 finding is on
debated, as different studiesdisease observed different 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.
Figure 1 Kaplan-Meier failure estimates for incident chronic is SUA. However,
Asterisk indicates true causality. not all patients with hyperuricaemia tions balanc
this
27 discussio
28
kidney diseaseKaplan-Meier
(CKD) to incident develop gout, and the reasons remain unclear.tion
Figure2. failuregout amongfor
estimates participants
incident Figure 3. Possible relationships between hyperuricemia as prop
who chronic
developed incident
kidney CKD
disease aftertothe
(CKD) baseline
incident visit
gout and thoseOf and
among
Furthermore,
foremost importance
chronic kidney is itwhether
is difcult to ascertain if hyperuricaemia
disease endowed with uricase and evolved with and need no
25
who participants
never developed CKD in the original Framingham
who developed incident CKD after the there
Heart is a preceded
biologic basis CKD
for this or whether
entity. extremely the
low reverse
plasma and is true.
tissue levels of To test ca
uricemia
Adapted from: data
Moeshows OW. in-
Posinguricthe question again: does se- quences, and
cohort.visit and those who never developed CKD in Humanchronic
baseline
Study histopathologic
the uric
inuence of SUA acid,
with which
the
acid nephropathy exist? J Am Soc Nephrol
are then rendered
relationship between
terstitial inflammation and fibrosis coex- verely hyperuricemic experimentally. result from
the original Framingham Heart Study cohort. 2010; 21:395-397.
isting with crystalline uric acid deposits, Similar findings in higher primates with conjunction
4 Adapted from: Wang W, Bhole VM, Krishnan E. Chronic which areWanginterpreted
W, et al. some
by BMJ as smok-
Open relative highdoi:10.1136/bmjopen-2014-006843
2015;5:e006843. normal plasma uric acid sitions. Tem
*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
are challenged by studies showing con- that are more challenging to unravel. GFR begets h
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
HYPERURICEMIA AND CKD KIDNEY MANIFESTATIONS
duction of hyperuricemia elevates BP sight into causality. The strength of asso- nation or red
and produces renal microvascular, glo- ciation is variable from study to study strongly sup
OF GOUT
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
largest study included 177,570 patients in the US Renal Dataorganism. URIC The ACID
mechanismsNEPHROLITHIASIS
by which studies. A recent article in this journal emerged in
System (USRDS) database followed over 25 years. Subjectsthese lesions Although gout patients
transpire are not yet have aprovided
known higheroneriskoffortheuric acid associa- ling, definiti
strongest
within the highest quartile of serum uric acid had a hazard even with theseformation
stone models in hand.
thanBased on without
people tions to date. Obermayr
gout, et al.11 prospec- ing a causativ
the primary
ratio of 2.14 for CKD, a level of risk that ranked third after the rodent database,
metabolic one will have
abnormality to promotes
that tively followed more lithiasis
uric acid than 21,000 is pa- ease is still n
proteinuria and severe obesity.27 However, causality cannotagree with the compelling view espoused tients for a median of 7 yr with different these years. W
excessive urinary acidity, since urine pH is the major deter-
be established solely from observational studies, especiallyby Henin and Johnson that the data are serum uric acid levels but the same base- general poin
minant of uric acid crystallization.28 Acidic urine is present
very close to satisfying Kochs criteria for line estimated GFR. They found mild hy- For the r
because 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
CKD and hyperuricemia is unclear. Accordingly, serum uric but is worse inthe stone formers, 29
and this is associated with dis- driving one
In contradistinction, human evi- doubled the risk for incident kidney
acid levels have not always been found to be an inde- decreased ammonium excretion. 30
Although hyperuricos-
dence 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
acidinduced factor
injury in the kidneyin causing uric tripled
(9.0 mg/dl) acid stones
the risk.inThe sig- negative ans
baseline kidney damage is considered. 28
some
is rather weak patient groups,
in comparison this
to the ro-is not the case
nificant for most
odds ratios people
survived albeit di- uric acid per
Observational studies and animal models suggest that dent with
data. Oneuric acid
needs to nephrolithiasis.
exercise height- 29
Likewise,
minished with the association
adjustments for baseline disease in hu
between
hyperuricemia itself is directly nephrotoxic, even before theened caution uric acid data
to extrapolate nephrolithiasis
gath- estimated and GFR,
the metabolic
gender, age,syn- drugs po- The impact,
clinical syndrome of gout develops, and may be a mecha- ered from drome is notsuch
species so much relatedtentially
as rodents to hyperuricemia,
altering serumbut uric rather
acid levels, the same ma
nism in the pathogenesis of hypertension, cardiovascular to excessive urinary acidity. Urinary pH and ammonium
disease, and CKD. But studies are conflicting and estab- 396 excretion
Journal of are directly
the American correlated
Society with the number of meta-
of Nephrology JA

lishing how hyperuricemia, hypertension, and CKD are bolic syndrome features, with a greater urinary acidity and
connected is difficult because of 1) the direct effect kidney lower ammonium excretion correlated to more features. In
function itself has on uric acid levels, and 2) the association fact, clinical studies have demonstrated that insulin resis-
of hyperuricemia with other causes of CKD, notably hy- tance is associated with excessive urinary acidity.28,31
pertension, confounding the interpretation of direction or
mechanism of the association.28 The possible pathogenic
relationships between hyperuricemia and CKD are repre-
sented in Figure 3.

3
KIDNEY MANIFESTATIONS OF LOWERING SERUM URIC ACID TO
HYPERURICEMIA TREAT GOUT IN THE SETTING OF CKD
URATE NEPHROPATHY The 2012 American College of Rheumatology (ACR)
Guidelines emphasizes both non-pharmacologic and phar-
Urate 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. Patholog- maintain 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 inter- oxidase 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
medullary urate deposits had not developed gout in life. 28,33
than 100 mg/day in moderate to severe CKD, followed by
Chapter 9 ClinicalFeaturesofGout 111
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 es-
tablished pharmacologic ULT, without interruption, during
an acute gout attack.17
The ACR recommends prophylaxis when initiating ULT be-
cause 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
Figure 4 Urate nephropathy. There is chronic tubulointerstitial nephri-
tis. Note the tubule distended by a collection of needle-like spaces, origi-
nally 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
LOWERING SERUM URIC ACID
Figure 9-11 This is chronic urate nephropathy with pale yellowish tan

TOAll rights
TREAT CKD
tophaceous deposits in the medulla. (Image Edward C. Klatt, MD, Savan-
.org/viewphoto.php?albumId=75676&;imageId=2862276.) nah, Georgia, USA. reserved. Available at http://library.med.utah.edu/
WebPath/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
Figure 4. even
with gout, Urate nephropathy
in the absence of renal stones, but is worse in With specific
lowering respect
serumto uric
urate acid
nephropathy
levels might (gouty
reduce the progres-
52
stone formers, and this is associated with a deficit of ammo- nephropathy), Sydenham9 describes morbific matter in
Adapted from:
nium excretion.55 Taylor WJ, Grainger R. In: Terkeltaub R, ed. sion of CKD. Data is based
what may be an early account of gouty nephopathy: mostly on observational stud-
Gout and Other
Although Crystal Arthropathies:
hyperuricosuria 1st ed.
is a very important Philadelphia,
factor in ies and small clinical trials,35-37 and a significant problem
The viscera in time are so much injured, from the stagna-
PA: Elsevier
leading to uricSaunders;
acid stones2012:105-120.
in some patient groups, this is
tion of thewith comparing
morbific their
matter therein, data,
that asideoffrom
the organs secre-methodology and
not present in most people with uric acid nephrolithiasis. confounding
tion no longer perform their disease states
functions, and
whence thetreatments,
blood, is the lack of
Hyperuricosuria may occur in rare metabolic conditions
overchargeduniformity
with vitiatedin defining
humours,hyperuricemia.
stagnates, and theLevy, et al conducted
OTHER DISEASES
such as Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome,
some glycogen storage diseases, or rare cases of URAT1 a large
gouty matter ceasesretrospective
to be thrown upon review of 111,992aspatients defined as
the extremities
formerly, so that at hyperuricemia
having length death frees himat afrom hisof
level misery.
> 7 mg/dL, and found
Less common
(SLC22A12) kidney manifestations of hyperuricemia in-
56 or GLUT9 (SLC2A9)57 mutations associated

clude: familial juvenile hyperuricemic nephropathy (FJHN),

with severe hypouricemia (see Chapter 4). In the that patients treated with uric acid lowering therapy (one
middle of the 20th century, it was well recognized
Recently, an association between the metabolic syn- that patientsof thegout
with following: allopurinol,
could frequently developfebuxostat,
renal impair-or probenecid),
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
disease (ESRD)appears
This association at an early
not toage, reduced
be due fractional
to the known asso-excretion
who achieved a serum uric
effective urate-lowering therapy or antihypertensive
acid < therapy,
6 mg/dL, showed a 37%
of uric acid, renal interstitial uric acid deposits,
ciation of hyperuricemia and the metabolic syndrome but and sporad- reduction in outcome events.
renal failure in patients with primary gout was not rare.
38
In a recent
For small prospec-
ic gouty
rather an arthritis;
associationcomplete
between anorunduly
partialacidic
hypoxanthine-guanine
urinary pH example, a tive, randomized,
case series open-label
of approximately 300 study
patientswithwith21 patients receiv-
and the metabolic syndrome. The
phosphoribosyltransferase principal
(HPRT) mechanisms
deficiency of
(Lesch-Nyhan ing febuxostat
mainly untreated gout from the and1950s
19 receiving
observed conventional
significant treatment, the
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
acid Kelley-Seegmiller
excretion and impaired syndromes, respectively);
buffering caused by inadequateacute changes,
uric in 1960, were observed in the large majority39of peo-
acid-related nephropathy, a condition
ammonium excretion. Urinary pH and ammonium excre- that is not usually hyperuricemic
59 patients with
ple with gout. However, whether these observations were CKD.
associated withcorrelated
tion are directly gout, butwithwiththea sudden,
number ofmassive
metabolicuric acid At a single
due to hyperuricemia center,
directly or topost hoc analysis
hypertension of 113 patients who had
that is often
load caused
syndrome by chemotherapy-induced
features, tumor lysis.
with more features being associated with 28 coexistent with gout is difficult to determine. Pathologically,
completed a 2-year, single-blind, randomized controlled
a more acidic urine and lower ammonium excretion. In stud- the kidneys of people with gout are characterized mainly by
ies using the hyperinsulinemic euglycemic clamp technique, trial of
changes typically allopurinol
associated with (56 patientsrenal
hypertensive received
disease:allopurinol and 57
insulin resistance was shown to be associated with excessive were in the control
advanced arteriosclerosis, group), showed
glomerulosclerosis, improved estimated
and intersti-
urinary acidity.58 glomerular
tial fibrosis (Figs. 9-10 andfiltration ratecrystal
9-11). Urate and reduced
depositioncardiovascular
is risk.40
observed, but the focal nature of that feature seems incon-
sistent with the diffuse nature of the renal disease.60 Further-
Urate 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 random- DISCLAIMER
ized clinical trial, is currently investigating the effect of
Information contained in this National
allopurinol in delaying the progression of CKD in type 1
Kidney Foundation educational resource
diabetes. The reason for creating this trial stems from
is based upon current data available
growing evidence that hyperuricemia may have a role in
at the time of publication. Information
the pathogenesis of diabetic nephropathy and the pro-
is intended to help clinicians become
gression of CKD observed in type 1 diabetes. This evidence
aware of new scientific findings and
includes epidemiologic data,41 and prospective data from
developments. This clinical bulletin is not
trials such as Reduction of Endpoints in Non-Insulin Depen-
intended to set out a preferred standard
dent Diabetes Mellitus with the Angiotensin II Antagonist
of care and should not be construed as
Losartan (RENAAL), in which lowering serum uric acid
one. Neither should the information be
through the use of losartan accounted for 20% of the reno-
interpreted as prescribing an exclusive
protection provided by this drug.41,42 Mounting evidence
course of management.
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

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

5
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Rheum. 2013;42:551-561.
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5. Y
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30 East 33rd Street
New York, NY 10016
800.622.9010
www.kidney.org
6 2015 National Kidney Foundation, Inc. 02-10-6972_CBF
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