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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 havereported 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

Although hyperuricemia and gout have beenknown to be associated with renal dysfunctionsince 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 goutmight cause kidney disease via the deposition of crystals

associated with inflammation, and hence manifest as an

extra-articular form of gout. Natural history studiesprior 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 renalbiopsies 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 characteristicfocal deposition of monosodium urate crystals in the

distal collecting duct and the medullary interstitium with

a secondary inflammatory reaction. This led to this lesionbeing described as chronic uric acid nephropathy (also

known as chronic urate nephropathyor gout nephrop-

athy). However, there was a debate of chronic urate

nephropathy as a true disease entity since focal deposi-tion of uric acid crystals could not be a mechanism to

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 didnot 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 considerit as a risk factor in the management of CKD.

FACTORS THAT

MODULATESERUMURIC ACID LEVELS

Uric acid is a weak acid trioxypurine (M.W. 168) that is

composed of a pyrimidine and imidazole substructurewith 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 acidby xanthine oxidoreductase. Both exogenous (present in

fatty meat, organ meats, and seafood) and endogenous

purines are major sources of xanthine and uric acid inhumans. 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 uricacid.

Approximately two thirds of total body urate is pro-

duced endogenously, while the remaining one third isaccounted for by dietary purines. The primary site of

excretion of uric acid is the kidney. The normal urinaryurate 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,

*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: [email protected]/ - see front matter

2011 Elsevier Inc. All rights reserved.

doi:10.1016/j.semnephrol.2011.08.009

Seminars in Nephrology, Vol 31, No 5, September 2011, pp 447-452 447
mailto:[email protected]:[email protected]:[email protected]


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secretion, and postsecretory reabsorption; the latter threeprocesses 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 pHof 7.4) is freely filtered in the glomerulus, the fractionalurate excretion is only 8% to 10% due to reabsorption in

proximal tubules in the normal adult. Some adaptationoccurs with renal disease, in which the fractional excre-tion of urate will increase to the 10% to 20%. Theremainder of uric acid excretion occurs through the gut,where uric acid is degraded by uricolytic bacteria. Thegastrointestinal tract may eliminate up to one-third of thedaily 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 increasein urate reabsorption in renal tubules and hyperurice-

mia.13

EPIDEMIOLOGICSTUDIES

Recently, Bellomo et al demonstrated the associationbetween uric acid and change in estimated glomerularfiltration rate (GFR) in a prospective cohort of 900healthy normotensive adult blood donors.14 Higher uric

acid levels were associated with subsequent worsening ofkidney function, and this association remained significantafter adjustment for theorized confounders such as bodymass 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 levelindependently increased the risk for new-onset kidney

disease.15 In addition, the Atherosclerosis Risks in Com-

munities and the Cardiovascular Health Study collecteddata from 13,338 participants with intact kidney functionand demonstrated that increased serum uric acid level isa modest, independent risk factor for incidental kidneydisease in the general population.16 A few large epide-miologic studies performed in Asian countries, Austriaand the United States have also shown that uric acid levelwas 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 canpredict 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 renaldisease in subjects with established CKD is more con-troversial. For example, some studies have found anelevated uric acid to be an independent risk factor forprogression 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 toModerate Kidney Disease Study29 could identify uricacid as an independent risk factor. In contrast, a recent

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 INTERVENTIONALSTUDIES

Studies in Chronic Kidney DiseaseThere 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 in113 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 thiswas 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-

448 D.-H. Kang and W. Chen


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dase-induced oxidants as being key in driving the vascu-lar effects associated with uric acid.36

Studies on VascularFunction and HypertensionVascular and endothelial function are known to have amajor role in driving CKD.37,38 In this regard, an elevatedserum uric acid is strongly associated with endothelialdysfunction.39-41 Zoccali et al demonstrated an inverserelationship between uric acid and acetylcholine-stimu-

lated vasodilatation in patients with untreated essentialhypertension, even after adjusting for differences in tra-ditional cardiovascular risk factors.41 Endothelial func-tion assessed by flow-mediated vasodilation (FMD) ofbrachial artery or acetylcholine-induced coronary bloodflow 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, metabolicsyndrome46 and even subjects with asymptomatic hyper-uricemia.47 Importantly, George et al demonstrated asteep dose-response relationship between allopurinol andits effect on endothelial function in chronic heart failure;however, the uricosuric agent probenecid had no effecton endothelial function despite a comparable reduction inserum uric acid levels.48 One possible explanation is thatsubjects with heart failure have high levels of xanthine

oxidase in their blood vessels, and hence a xanthineoxidase inhibitor may be more effective at lowering uricacid levels inside the endothelial cell as compared to a

uricosuric agent such as probenecid. It is also possiblethat the benefit is due to the inhibition of xanthine oxi-dase associated oxidants as opposed to lowering uricacid.

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 adolescentswith essential hypertension. In particular, a randomizedcontrol trial found that allopurinol treatment could reduceblood pressure in adolescents with newly diagnosed hy-pertension, which resulted in normal blood pressure in

66% of adolescents with essential hypertension versus3% of controls.50 Thus, there is emerging evidence that

lowering uric acid with allopurinol may have a variety ofbenefits, including on endothelial function, blood pres-sure, and renal function. However, to date all studieshave been limited and should be viewed as pilot innature.

EXPERIMENTAL STUDIES

Establishment of an animal model of hyperuricemia us-ing uricase inhibitors have deepened our understandingregarding uric acid-related renal disease and its mecha-nisms. Hyperuricemic rats showed preglomerular arterial

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 withactivation 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

Uric acid and CKD 449


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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 asa consequence of an altered proliferation and senescence

of vascular cells, an induction of local oxidative stressand inflammation with an activation of RAS, followed by

impaired peritubular capillary circulation and renal isch-

emia. Uric acid-induced phenotypic transition of renaltubular 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 relatedto declining glomerular filtration. Nonetheless, there are

still controversies regarding the causative role of uricacid 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 serumuric acid should be targeted for renoprotection with uric

acid-lowering therapy. Given the worldwide epidemic ofCKD 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

renal function, cardiovascular disease and mortality in

CKD patients.

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Uric Acid

ro erat on o

Inhibition of proliferation of VEC with

cell senescence

Activation of local COX-2 & RAS

Induction of inflammatory reaction

Decrease in NO production

Induction of oxidative stress

Preglomerular ArteriopathyEMT of Renal

Tubular Cells

Production of ECMImpairment of peritubular

circulation

Renal ischemia

Ineffective

autoregulation of

glomerular pressure

Glomerular

HypertensionActivation of RAS

Renal fibrosis

Tubulointerstitial

Inflammation

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, nitricoxide, EMT, epithelial-to-mesenchymal transition, ECM, extracellular matrix.



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