Uric Acid and Chronic Kidney Disease:

New Understanding of an Old Problem

Duk-Hee Kang, MD, PhD,* and Wei Chen, MD

Summary: Although an elevation of serum uric acid level is often associated with chronic kidney disease (CKD),
it remains controversial whether hyperuricemia per se is a true risk factor for the development or aggravation of
CKD. Recent epidemiologic studies in healthy populations or in subjects with established kidney disease have
reported the independent role of uric acid in lowering glomerular filtration rate and increasing the risk for new-onset
kidney disease. Furthermore, lowering uric acid in patients with established renal disease has been reported to
stabilize renal function independent of other confounders, suggesting a causative role of elevated uric acid in
progression of CKD, rather than as an incidental finding related to CKD severity. In this manuscript we will discuss
the potential role of uric acid in the development and aggravation of CKD based on epidemiologic, clinical and
experimental studies. Given the worldwide epidemic of CKD, the importance of identifying modifiable risk factors
of CKD, and the clinical implication of hyperuricemia in CKD, we propose large randomized clinical trials to
investigate whether uric acid-lowering therapy can slow the progression of CKD.
Semin Nephrol 31:447-452 2011 Elsevier Inc. All rights reserved.
Keywords: hyperuricemia, allopurinol, gout, chronic kidney disease

INTRODUCTION nephropathy as a true disease entity since focal deposi-

tion of uric acid crystals could not be a mechanism to

A lthough hyperuricemia and gout have been

known to be associated with renal dysfunction
since the late 19th century,1 there has been debate
over whether uric acid may have a true pathogenic role in
renal disease. Originally the focus was whether gout
might cause kidney disease via the deposition of crystals
associated with inflammation, and hence manifest as an
extra-articular form of gout. Natural history studies
prior to the availability of uric acid-lowering drugs re-
ported that up to 25% of gouty subjects developed pro-
teinuria, 50% developed renal insufficiency, and 10% to
25% developed end-stage renal disease.2,3 Both renal
biopsies and renal tissue at autopsy showed relatively
nonspecific features consisting of arteriolosclerosis, glo-
merulosclerosis, and tubulointerstitial fibrosis.3 Interest-
ingly, many of these biopsies also showed characteristic
focal deposition of monosodium urate crystals in the
distal collecting duct and the medullary interstitium with
a secondary inflammatory reaction. This led to this lesion
being described as chronic uric acid nephropathy (also
known as chronic urate nephropathyor gout nephrop-
athy). However, there was a debate of chronic urate
*Division of Nephrology, Department of Internal Medicine, Ewha
Womans University School of Medicine, Ewha Medical Research
Center, Seoul, Korea.
Division of Nephrology, University of Colorado, CO.
This work was supported by a National Research Foundation Grant
funded by the Korean government (MEST) (2010-0019866).
Address correspondence to Duk-Hee Kang, MD, PhD, Division of
Nephrology, Ewha University School of Medicine, 911 Mok-dong
Yangchun-ku, Seoul 158-710, Korea; Tel 82-2-2650-2870; Fax 82-
2-2655-2076; E-mail: dhkang@ewha.ac.kr
0270-9295/ - see front matter
2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.semnephrol.2011.08.009
explain the diffuse renal injury observed in biopsies of
gouty patients with CKD.4-6 Urate crystals could also be
identified in the kidneys of autopsied subjects who did
not have evidence for kidney disease. Hence, gouty ne-
phropathy was viewed as a non-entity7, and since then
most nephrologists do not measure uric acid or consider
it as a risk factor in the management of CKD.
FACTORS THAT
MODULATE SERUM URIC ACID LEVELS
Uric acid is a weak acid trioxypurine (M.W. 168) that is
composed of a pyrimidine and imidazole substructure
with oxygen molecules, which is produced primarily in
the liver, muscle, and intestine.8 The immediate precursor
of uric acid is xanthine, which is degraded into uric acid
by xanthine oxidoreductase. Both exogenous (present in
fatty meat, organ meats, and seafood) and endogenous
purines are major sources of xanthine and uric acid in
humans. Fructose, such as from added sugars and fruits,
is another major source of uric acid. Fructose is unique
among sugars in that its phosphorylation by fructokinase
results in a transient reduction in ATP levels in the cell.
In turn, the AMP generated is acted on by AMP deami-
nase to form IMP which is then further degraded to uric
acid.
Approximately two thirds of total body urate is pro-
duced endogenously, while the remaining one third is
accounted for by dietary purines. The primary site of
excretion of uric acid is the kidney. The normal urinary
urate excretion in the range of 250 to 750 mg per day,
approximately 70% of the daily urate production.9 The
classic paradigm of uric acid excretion consists of a
four-step model with glomerular filtration, reabsorption,

Seminars in Nephrology, Vol 31, No 5, September 2011, pp 447-452 447

448
secretion, and postsecretory reabsorption; the latter three
processes occur in the proximal convoluted tubule.10
More recently emphasis has focused on the role of spe-
cific transporters, such as URAT1, SLC2A9, and oth-
ers.11,12 Although urate (the form of uric acid at blood pH
of 7.4) is freely filtered in the glomerulus, the fractional
urate excretion is only 8% to 10% due to reabsorption in
proximal tubules in the normal adult. Some adaptation
occurs with renal disease, in which the fractional excre-
tion of urate will increase to the 10% to 20%. The
remainder of uric acid excretion occurs through the gut,
where uric acid is degraded by uricolytic bacteria. The
gastrointestinal tract may eliminate up to one-third of the
daily uric acid load in the setting of CKD.
Overall, serum uric acid level is determined by the
balance between generation and excretion of uric acid.
Obesity, insulin resistance, hypertension and use of di-
uretics are several conditions associated with an increase
in urate reabsorption in renal tubules and hyperurice-
mia.13
EPIDEMIOLOGIC STUDIES
Recently, Bellomo et al demonstrated the association
between uric acid and change in estimated glomerular
filtration rate (GFR) in a prospective cohort of 900
healthy normotensive adult blood donors.14 Higher uric
acid levels were associated with subsequent worsening of
kidney function, and this association remained significant
after adjustment for theorized confounders such as body
mass index (BMI), blood pressure and urine albumin-
creatinine ratio.14 A recent study in 21,475 healthy par-
ticipants who were followed up prospectively for a me-
dian of 7 years also revealed that increased uric acid level
independently increased the risk for new-onset kidney
disease.15 In addition, the Atherosclerosis Risks in Com-
munities and the Cardiovascular Health Study collected
data from 13,338 participants with intact kidney function
and demonstrated that increased serum uric acid level is
a modest, independent risk factor for incidental kidney
disease in the general population.16 A few large epide-
miologic studies performed in Asian countries, Austria
and the United States have also shown that uric acid level
was a major predictor for the development of incident
kidney disease.17-22 Studies of subjects with type 1 dia-
betes have also found that an elevated uric acid can
predict the development of either overt diabetic nephrop-
athy23 or the development of micro- and macroalbumin-
uria.24
The role of uric acid in predicting progression of renal
disease in subjects with established CKD is more con-
troversial. For example, some studies have found an
elevated uric acid to be an independent risk factor for
progression of kidney disease in kidney transplant pa-
tients whereas others have not.25-27 Neither the Modifi-
cation of Diet in Renal Disease Study28 nor the Mild to
Moderate Kidney Disease Study29 could identify uric
acid as an independent risk factor. In contrast, a recent
D.-H. Kang and W. Chen
study in middle-aged and old Taiwanese found that ele-
vated uric acid level increased the risk of renal disease
only in stage 3 CKD but not with stage 4 or 5 CKD.30
These studies suggest that once CKD is advanced that the
progression of renal disease may be driven by so many
additional factors that the role of uric acid is not signif-
icant.
CLINICAL INTERVENTIONAL STUDIES
Studies in Chronic Kidney Disease
There have been limited number of studies to examine the
effect of uric acid-lowering in the development or progres-
sion of CKD. Kanbay et al. reported that treatment of
asymptomatic hyperuricemia improved renal function.31
Likewise, Siu et al. reported that the treatment of asymp-
tomatic hyperuricemia delayed disease progression with a
lesser increase in blood pressure with 12-month-treatment
of allopurinol in patient with CKD.32 More recently, Goi-
coechea et al performed a randomized, prospective study in
113 patients with estimated GFR (eGFR) 60 ml/min and
demonstrated that allopurinol (100 mg/day) is able to slow
the progression of renal disease after a mean time of 23.4
7.8 months.33 No changes in blood pressure or in albumin-
uria induced by allopurinol have been observed. Interest-
ingly, allopurinol treatment also reduces cardiovascular and
hospitalization risk in these subjects.
Interestingly, there is some evidence that the effect of
allopurinol may mimic the effects of agents that block the
renin-angiotensin system (RAS). For example, Talaat
performed an interesting study in which he withdrew
allopurinol from subjects with CKD, and found that this
was associated with worsening hypertension, proteinuria
and loss of eGFR only in those subjects not taking ACE
inhibitors or other agents that block the RAS.34 Likewise,
a small clinical trial of allopurinol in Chinese subjects
with early IgA nephropathy who were not receiving ACE
inhibitors demonstrated that allopurinol tended to reduce
GFR acutely, but then was followed by stabilization of
the slope in GFR. This finding is consistent with exper-
imental studies suggesting that lowering uric acid may
lower glomerular pressure via angiotensin II-dependent
mechanisms (W Chen, unpublished).
While these studies suggest a potential benefit of low-
ering uric acid in subjects with CKD, it is important to
realize these are small clinical studies and that major
clinical trials need to be performed prior to routinely
lowering uric acid in subjects with CKD. This is partic-
ularly true since allopurinol can induce a hypersensitivity
syndrome that can be fatal.35 Second, the above studies
do not separate whether the benefit of lowering uric acid
with allopurinol is due to the reduction in uric acid levels
per se or due to other effects of allopurinol. For example,
allopurinol also blocks the production of oxidants that are
generated during the conversion of xanthine to uric acid
by xanthine oxidase. Some studies, especially in the
cardiovascular literature, suggest the latter xanthine oxi-
Uric acid and CKD
dase-induced oxidants as being key in driving the vascu-
lar effects associated with uric acid.36
Studies on Vascular
Function and Hypertension
Vascular and endothelial function are known to have a
major role in driving CKD.37,38 In this regard, an elevated
serum uric acid is strongly associated with endothelial
dysfunction.39-41 Zoccali et al demonstrated an inverse
relationship between uric acid and acetylcholine-stimu-
lated vasodilatation in patients with untreated essential
hypertension, even after adjusting for differences in tra-
ditional cardiovascular risk factors.41 Endothelial func-
tion assessed by flow-mediated vasodilation (FMD) of
brachial artery or acetylcholine-induced coronary blood
flow was inversely correlated with serum uric acid lev-
els.39-41 Furthermore, allopurinol treatment has been re-
ported to improve peripheral or cerebrovascular endothe-
lial function in patients with chronic heart failure,42,43
recent ischemic stroke,44 type 2 diabetes45, metabolic
syndrome46 and even subjects with asymptomatic hyper-
uricemia.47 Importantly, George et al demonstrated a
steep dose-response relationship between allopurinol and
its effect on endothelial function in chronic heart failure;
however, the uricosuric agent probenecid had no effect
on endothelial function despite a comparable reduction in
serum uric acid levels.48 One possible explanation is that
subjects with heart failure have high levels of xanthine
oxidase in their blood vessels, and hence a xanthine
oxidase inhibitor may be more effective at lowering uric
acid levels inside the endothelial cell as compared to a
uricosuric agent such as probenecid. It is also possible
that the benefit is due to the inhibition of xanthine oxi-
dase associated oxidants as opposed to lowering uric
acid.
Hypertension is also a well-established risk factor for
CKD.49 Hyperuricemia is known to be associated with an
elevation of blood pressure despite a continuing contro-
versy regarding its causative role.50 A recent study sug-
gests uric acid may have a causative role in adolescents
with essential hypertension. In particular, a randomized
control trial found that allopurinol treatment could reduce
blood pressure in adolescents with newly diagnosed hy-
pertension, which resulted in normal blood pressure in
66% of adolescents with essential hypertension versus
3% of controls.50 Thus, there is emerging evidence that
lowering uric acid with allopurinol may have a variety of
benefits, including on endothelial function, blood pres-
sure, and renal function. However, to date all studies
have been limited and should be viewed as pilot in
nature.
EXPERIMENTAL STUDIES
Establishment of an animal model of hyperuricemia us-
ing uricase inhibitors have deepened our understanding
regarding uric acid-related renal disease and its mecha-
nisms. Hyperuricemic rats showed preglomerular arterial
449
disease, renal inflammation and hypertension via an ac-
tivation of the RAS and COX-2 systems.51,52 Uric acid is
also a mitogen for vascular smooth muscle cells whereas
it inhibits a proliferation of vascular endothelial cells. Rat
aortic vascular smooth muscle cells showed de novo
expression of COX-2 mRNA after incubation with uric
acid.52 Incubation of the vascular smooth muscle cells
with either a COX-2 inhibitor or with a TX-A2 receptor
inhibitor prevented the proliferative response to uric acid.
COX-2 was also shown to be expressed de novo in the
preglomerular vessels of animal model of CKD with
hyperuricemia, and its expression correlated both with
the uric acid levels and with the degree of smooth muscle
cell proliferation. These findings suggest a critical role
for uric acid-mediated COX-2 generated thromboxane in
vascular smooth muscle cell proliferation in an animal
model of CKD. It is also likely that angiotensin II con-
tributes to uric acid-induced vasculopathy. Preglomerular
vasculopathy in rats with oxonic acid-induced hyperuri-
cemia can be largely prevented by blocking the RAS.51
Consistent with these in-vivo findings, uric acid mediated
effects on vascular smooth muscle and endothelial cell
can be partially inhibited by blocking the angiotensin II
type 1 receptor.51 Therefore, both angiotensin II and
COX-2 are involved in the vascular proliferation and
inflammation observed in in-vitro and in-vivo animal
studies.
Once thickening of the afferent arterioles and macro-
phage infiltration in vessel wall was induced, preglo-
merular vasculopathy may potentiate renal injury by
causing ischemia to the postglomerular circulation. The
reduction in lumen diameter could also provide a stimu-
lus for the increase in renin expression we observed, and
might also contribute to the development of the marked
hypertension in these rats.51,53,54 Furthermore, there is
evidence that the arteriolopathy also leads to ineffective
autoregulation and increased transmission of systemic
pressures to the glomerulus,55 which can also potentiate
renal damage.
Uric acid also induced the proinflammatory cytokine,
monocyte chemoattractant protein-1 (MCP-1) and de
novo expression of C-reactive protein (CRP) in vascular
smooth muscle and endothelial cells, which was further
shown to be due to direct entry of uric acid into cells with
activation of mitogen activated protein kinase (MAPK)
and nuclear transcription factor (NF-kB).56,57 In addition,
uric acid can become pro-oxidative under certain circum-
stances.58 The prooxidative effects are primarily medi-
ated by intracellular uric acid, and can be shown in
endothelial cells, vascular smooth muscle cells, renal
tubular cells, adipocytes, and cardiac fibroblasts.59-63 On
the other hand, in the extracellular environment, uric acid
may function as an antioxidant, particularly as a scaven-
ger of peroxynitrite.64 The different effects of uric acid
may depend on the host environment.
Recent data also suggested the possibility of direct
effect of uric acid on renal tubular cells. Uric acid per se
450
P
Proliferation
lif ti off VSMC
Inhibition of proliferation of VEC with
cell senescence
Activation of local COX-2 & RAS
Induction of inflammatoryy reaction
Decrease in NO production
Induction of oxidative stress
Preglomerular Arteriopathy
Ineffective Impairment of peritubular
autoregulation of circulation
glomerular pressure
Renal ischemia
Glomerular
Hypertension
Activation of RAS
Figure 1. Summary of potential mechanisms of uric acid-induced kidney disease proposed by experimental data from hyperuricemic rats.
VSMC, vascular smooth muscle cells, VEC, vascular endothelial cells, COX-2, cyclooxygenase-2, RAS, renin-angiotensin system, NO, nitric
oxide, EMT, epithelial-to-mesenchymal transition, ECM, extracellular matrix.
may induce phenotypic transition of cultured renal tubu-
lar cells, as epithelial-to-mesenchymal transition (EMT)
can be demonstrated in the kidneys of hyperuricemic
rats.65 Given the consideration of EMT as one of the
earliest phenomena of renal fibrosis, 66 it will be inter-
esting to further investigate the mechanism of EMT of
renal tubular cells as a novel mechanism of uric acid-
induced renal disease.
Taking all into consideration, uric acid may induce
renal disease via an induction of afferent arteriopathy as
a consequence of an altered proliferation and senescence
of vascular cells, an induction of local oxidative stress
and inflammation with an activation of RAS, followed by
impaired peritubular capillary circulation and renal isch-
emia. Uric acid-induced phenotypic transition of renal
tubular cells also could be important (Figure 1).
CONCLUSIONS
There is accumulating epidemiologic, clinical and exper-
imental evidence supporting hyperuricemia as a true risk
factor of CKD rather than an incidental findings related
to declining glomerular filtration. Nonetheless, there are
still controversies regarding the causative role of uric
acid in the development or aggravation of CKD with
conflicting results in different studies. There is no con-
sensus yet whether we need to treat asymptomatic hy-
peruricemia in CKD patients or whether a level of serum
uric acid should be targeted for renoprotection with uric
acid-lowering therapy. Given the worldwide epidemic of
CKD population, it is critical to identify modifiable,
novel risk factors of CKD and treat them adequately.
Uric acid may be one of the ignored risk factors of CKD.
We recommend large randomized clinical trials to eval-
uate the effect of uric acid reduction on progression of
D.-H. Kang and W. Chen
Uric Acid
EMT of Renal
Tubular Cells
Production of ECM
Tubulointerstitial
Inflammation
Renal fibrosis
renal function, cardiovascular disease and mortality in
CKD patients.
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