review article the role of uric acid in kidney fibrosis ...another animal model of...

Review ArticleThe Role of Uric Acid in Kidney Fibrosis ExperimentalEvidences for the Causal Relationship

Il Young Kim12 Dong Won Lee12 Soo Bong Lee12 and Ihm Soo Kwak13

1 Division of Nephrology Department of Internal Medicine Pusan National University School of MedicineYangsan 626-770 Republic of Korea

2 Research Institute for Convergence of Biomedical Science and Technology Pusan National University Yangsan HospitalYangsan 626-770 Republic of Korea

3Medical Research Institute Pusan National University Hospital Busan 602-739 Republic of Korea

Correspondence should be addressed to Soo Bong Lee sbleemdpusanackr

Received 27 February 2014 Revised 5 April 2014 Accepted 21 April 2014 Published 5 May 2014

Academic Editor Keizo Kanasaki

Copyright copy 2014 Il Young Kim et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Hyperuricemia is a common finding in chronic kidney disease due to decreased uric acid clearance The role of uric acid as arisk factor for chronic kidney disease has been largely debated and recent studies suggested a role of uric acid in the causationand progression of kidney fibrosis a final common pathway in chronic kidney disease Uric acid and xanthine oxidase maycontribute to kidney fibrosismainly by inducing inflammation endothelial dysfunction oxidative stress and activation of the renin-angiotensin system Besides hyperuricemia induces alterations in renal hemodynamics via afferent arteriolopathy and contributesto the onset and progression of kidney fibrosis Xanthine oxidase inhibitors may prevent kidney damage via lowering uric acidandor inhibiting xanthine oxidase However there is still no sufficient evidence from interventional clinical researches supportingthe causal relationship between uric acid and kidney fibrosisThe effect and role of xanthine oxidase inhibitors in preventing kidneyfibrosis and chronic kidney disease progression must be further explored by performing future large scale clinical trials

1 Introduction

Regardless of the underlying etiology most forms of chronickidney disease (CKD) are characterized by progressive fibro-sis as a final common pathway which eventually affects allsubstructures of the kidney leading to a final consequence ofend-stage renal disease Although there has been a great dealof research a comprehensive understanding of the patho-genetic mechanisms of kidney fibrosis remains uncertainand this hampers the development of effective therapeuticstrategies [1]

Uric acid (UA) is the final breakdown product of purinedegradation in humans and elevated serum UA level hyper-uricemia is causative in gout and urolithiasis due to the for-mation and deposition of monosodium urate crystals Hype-ruricemia is a common finding in CKD due to decreasedUA clearance Its role as a risk factor for CKD progressionhas been largely debated and it was primarily considered

as a marker or epiphenomenon of kidney damage [2 3]However during the last 2 decades accumulating evidenceshave suggested a role of UA in the causation or progression ofcardiovascular diseases and CKD [3ndash9] Therefore UA low-ering therapy with xanthine oxidase (XO) inhibitors whichare already being widely used in the treatment of gout couldbe promising for preventing the progression of CKD evenin patients without hyperuricemia however solid clinicalevidence is still lacking To promote large scale prospectiveclinical trials it is essential to accumulate experimentalevidences for the cause-effect relationship between UA andkidney fibrosis

In this review after providing a brief background con-cerning UA physiopathology we will focus on the mechanis-tic role of UA in kidney fibrosis We will also review the roleof XO and the effect of XO inhibitors in preventing kidneyfibrosis and their associated mechanisms

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 638732 9 pageshttpdxdoiorg1011552014638732

2 BioMed Research International

AMP IMP

Adenosine Inosine

Hypoxanthine

GMP

Guanosine

Guanine

Xanthine Uric acid

MSU

Xanthine oxidase

Xanthine oxidase

Allopurinolfebuxostat

1 11

2

3

4

4

5H O2 2 H O2 2H2O2 O2

H2O2 O2

Figure 1 The pathway of purine nucleotides degradation in humans showing the competitive inhibition of uric acid formation by xanthineoxidase inhibitors and the site of action AMP adenosine monophosphate GMP guanosine monophosphate IMP inosine monophosphateMSU monosodium urate A 51015840-nucleotidase B AMP deaminase C adenosine deaminase D purine nucleoside phosphorylase Eguanine deaminase

2 Physiopathology of Uric Acid

Cell turnover leads to the production of adenosine inosineand guanosine They degrade to hypoxanthine and xanthinewhich are the substrates for the widely distributed XO inthe formation of UA XO catalyzes the oxidation of purinesubstrates xanthine and hypoxanthine producing both UAand reactive oxygen species (ROS) Thus XO is one of themajor enzymatic sources of ROS Allopurinol and febuxostatare inhibitors of XO and they reduce uric acid and ROSformation (Figure 1) [10]

UA is the oxidation end-product of purine metabolism inhumans and higher primates Most other mammals exceptfor the Dalmatian dogs can degrade UA further to water-soluble allantoin with the enzyme uricase and as a resultserum urate levels are about 10 of those in humans [9 11]However in humans and higher primates mutations in theuricase gene occurred during evolution and making theenzyme nonfunctional resulted in higher levels of serumUAthan in other mammals [12]

Urates are the ionized form of UA and at a physiologicpH of 74 over 95 of UA dissociates into urates with98 existing as monosodium urate The serum urate leveldepends on dietary purines the breakdown of endogenouspurines and the renal and intestinal excretion of urateHyperuricemia is defined as the accumulation of serumUA beyond its solubility point in water (68mgdL) andit develops due to UA overproduction undersecretion orboth [13] The dominating factor contributing to hyper-uricemia is underexcretion of urate [11] Under normalconditions 70 of the UA produced is eliminated in theurine and the remaining UA is removed via biliary secretion

In the kidney urate is easily filtered through the glomerulusand subsequently reabsorbed by the proximal tubule cells ofthe kidney and after further absorption about 10 of urateis finally excreted [14] An anion exchanger and a voltage-dependent pathway seem to be the mechanisms involved inurate transport [15]

Allopurinol a purine inhibitor of XO has been con-ventionally used for urate-lowering therapy to inhibit UAsynthesis A novel urate-lowering drug febuxostat is a potentnonpurine selective inhibitor of XO and it inhibits both thereduced and oxidized forms of the enzyme in contrast toallopurinol that inhibits the reduced form of the enzyme only[16 17] Febuxostat is metabolizedmainly by glucuronidationand oxidation in the liver has its dual (urinary and fecal)pathways in excretion (urinary and fecal excretion rates491 and 449 resp) and is effective and well tolerated inpatients withmild tomoderate renal and hepatic impairment[18 19] Animal studies have demonstrated that febuxostathas a greater UA-lowering effect than allopurinol [20 21]Febuxostatrsquos chemical structure does not resemble a pyrim-idine or purine and is unlike that of allopurinol [22] It doesnot inhibit other enzymes involved in purine or pyrimidinemetabolism [23]

Studying the role ofUA in kidney fibrosis a processwhicheventually leads to CKD is very difficult since uric acid isexcreted primarily by the kidney and hence a decrease in theglomerular filtration rate (GFR) is inevitably accompanied bya rise in the serumUA level As such studies in experimentalanimals in which serum UA can be modulated are critical tounderstand whether there is a role for UA in the causation orprogression of CKD [7]

BioMed Research International 3

3 Experimental Studies Supportingthe Roles of Uric Acid and XanthineOxidase in Kidney Fibrosis

In the past hyperuricemia was thought to cause CKDthe so-called urate nephropathy by the deposition of uratecrystals in the renal interstitium This results in a chronicinflammatory response and in progressive tubulointerstitialinjury in a similarmanner as seenwith tophi in gouty arthritis[24]However the pathologic role of hyperuricemia in kidneydisease by a crystal-independentmechanism is somewhat lessclear

31 Hyperuricemic Rat Models and Types of Kidney InjuryGenerating hyperuricemia in laboratory animals proved tobe difficult due to the fact that most mammals have theuricase enzyme Rodentmodels inwhich the uricase genewasknocked out showed renal failure due to extensive tubularcrystal deposition and finally death [25] An alternativemodel with milder degree of hyperuricemia without crystaldeposition which is more applicable to human disease wasdeveloped using uricase inhibitor oxonic acid (OA) [26ndash29]It is also possible to lower serum UA levels using the XOinhibitors such as allopurinol and febuxostat

After the year 2001 when the hyperuricemic rat modelwas developed by using OA [26] and until recently therehave been accumulating experimental evidences that hype-ruricemia induced renal injury which may be prevented bylowering serum UA levels with XO inhibitors The first studyusing OA-induced hyperuricemic rat model demonstratedthat hyperuricemia induced systemic hypertension as wellas ischemic type of kidney injury with collagen depositionmacrophage infiltration and increase in tubular expressionof osteopontin documented via immunohistochemical stainsThe kidneys were devoid of urate crystals and were normalby light microscopy Blood pressure was lowered by reduc-ing serum UA levels with allopurinol Hyperuricemic ratstreated with OA also showed an increase in juxtaglomerularrenin and a decrease in macula densa neuronal nitric oxide(NO) synthase Both the kidney injury and hypertensionwere attenuated by treatment with renin-angiotensin system(RAS) blocker (enalapril) or a substrate for endothelial NOsynthase (L-arginine) This study suggested that UA inducedhypertension and renal injury via a crystal-independentmechanism with the activation of RAS and inhibition ofNO synthase [26] Another study demonstrated that hype-ruricemia induced arteriolopathy of the afferent arterioleby a blood pressure-independent mechanism In this studyhyperuricemic rats fed OA showed hypertension and afferentarteriolar thickening Allopurinol prevented hyperuricemiahypertension and arteriolopathy Controlling blood pressurewith hydrochlorothiazide did not prevent hyperuricemiaand arteriolopathy suggesting that hyperuricemia-inducedarteriolopathy was not mediated by blood pressure Thisstudy also showed that arteriolopathy was mediated by thedirect effect of UAon proliferation of vascular smoothmusclecells with activation of RAS [27]

In another rat model with dietary intake of adeninewhichmay be the source of the UA as a purine base adenine-fed rats showed hyperuricemia [30 31] Adenine-fed ratsalso showed increased kidney inflammation (TNF-120572) fibrotic(TGF-120573) and oxidative (HO-1) markers along with patho-logically confirmed kidney fibrosis Lowering of UA levelswith allopurinol reversed the kidney damage suggesting thatUA played a major role in the pathogenesis of kidney fibrosis[30] Another animal model of tubulointerstitial nephritis(TIN) induced by excessive adenine intake exhibited sig-nificant renal dysfunction and enhanced cellular infiltrationaccompanied by collagen deposition It also showed highergene and protein expression of proinflammatory cytokinesTreatment with allopurinol led to reduced levels of uric acidoxidative stress and collagen deposition and a downregula-tion of the nuclear factor-kB (NF-kB) signaling pathway [31]

Based on the growing evidence that lowering UA lev-els with allopurinol prevented renal injury induced byhyperuricemia the role of febuxostat in preventing kidneyinjury was investigated In OA-induced hyperuricemic ratsfebuxostat lowered UA levels and ameliorated systemic andglomerular hypertension as well as preglomerular arteri-olopathy In normal rats without hyperuricemia febuxostattended to lowerUA levels andhadno effect on bloodpressureglomerular pressure and afferent arteriole morphology [32]

32 Systemic and Glomerular Hypertension in HyperuricemiaThere are some experimental studies that demonstrated therelationship between UA and renal hemodynamics In onestudy hyperuricemic rats fed OA not only developed sys-temic hypertension but also glomerular hypertensionHyper-uricemic rats showed increased glomerular capillary pressurewith afferent arteriole thickening Allopurinol preventedhyperuricemia systemic and glomerular hypertension andarteriolopathy Glomerular capillary pressure and arteriolarthickening correlated with serum UA and systolic bloodpressure This study suggested that glomerular hypertensionmight be mediated by insufficient vasoconstriction of theafferent arteriole to systemic hypertension allowing thetransmission of systemic pressure to the glomerular capillarytuft [33] In another study hyperuricemia induced by OAresulted in renal cortical vasoconstriction and glomerularhypertension due to afferent arteriole thickening in normaland remnant kidney rats Allopurinol prevented structuraland functional alterations in both normal and remnantkidney ratsThis study suggested that hyperuricemia-inducedglomerular alterations caused renal ischemia which in turninduced tubulointerstitial inflammation and fibrosis [28]

33 Renal Progression in Animal Models of Chronic KidneyDisease Hyperuricemia also contributed to renal progres-sion in animal models of CKD In 56 nephrectomy remnantkidney model remnant kidney rats fed OA showed moresevere renal failure proteinuria and histologic findings(thickening of the preglomerular arteries glomerulosclerosisand interstitial fibrosis) compared to remnant kidney ratswithout hyperuricemia Allopurinol reduced serumUA levels


and prevented the functional and histologic changes in rem-nant kidney rats fed OA This study also demonstrated thathyperuricemia accelerated renal progression by increasingrenin expression in the renal cortex and cyclooxygenase-2 (COX-2) expression in the afferent arteriole In partic-ular this study showed that increased COX-2 expressioninduced by hyperuricemia was associated with proliferationof vascular smooth muscle cells in preglomerular arteries[29] In another 56 nephrectomy rat model remnant kid-ney rats treated with OA developed hyperuricemia renalvasoconstriction and glomerular hypertension in associationwith further aggravation of afferent arteriolopathy comparedto remnant kidney rats that were not treated with OAFebuxostat prevented hyperuricemia and ameliorated renalinjury in remnant kidney rats treated with OA Interestinglyfebuxostat had a comparable beneficial effect in both rem-nant kidney rats with hyperuricemia (treated with OA) andremnant kidney rats without hyperuricemia (not treated withOA) [34]

34 Exacerbation of Renal Injury in Animal Models ofCyclosporine and Diabetic Nephropathy Hyperuricemia hasalso been known to exacerbate renal injury in some animaldisease models including cyclosporine (CsA) and diabeticnephropathy Hyperuricemia frequently complicated CsAtherapy In one study using a model of CsA nephropathythe rats developed hyperuricemia with arteriolar hyalinosistubular injury and interstitial fibrosis CsA nephropathyrats fed OA showed higher UA levels with more severehistologic findings compared to CsA nephropathy rats thatwere not treated with OA This study also demonstratedthat the mechanism did not involve intrarenal urate crystaldeposition and appeared to involve activation of RAS andinhibition of intrarenalNOproduction [35] In another studyCsA-treated rats developed hyperuricemia with arteriolarhyalinosis tubular atrophy interstitial fibrosis increasedcell proliferation and decreased vascular endothelial growthfactor (VEGF) Treatment with allopurinol or a uricosuricbenzbromarone reduced the severity of the kidney injuryBoth drugs provided comparable protection and the similarprotection observedwith both drugs suggests that the effect isassociatedmore with lowering UA levels than the antioxidanteffect of allopurinol [36] Hyperuricemia has recently beenrecognized to be a risk factor for nephropathy in the diabeticsubject Diabetic (dbdb) mice developed hyperuricemiaalbuminuria mesangial matrix expansion and mild tubu-lointerstitial disease Allopurinol treatment not only reducedUA levels but also reduced albuminuria and amelioratedtubulointerstitial injury The mechanism for protection wasshown to be due to a reduction in inflammatory cellsmediated by a reduction in ICAM-1 expression by tubularepithelial cells [37] In another diabetic nephropathy modelusing KK-A(y)Ta mice lowering UA levels with allopurinolattenuated transforming growth factor- (TGF-) 1205731-inducedprofibrogenic progression in the mice suggesting that low-ering serum UAmay be an effective therapeutic interventionto prevent the progression of diabetic nephropathy [38]

35 Oxidative Stress and Endothelial Dysfunction in Hype-ruricemia While UA has been reported to be a potentantioxidant in the extracellular fluid [39] it has prooxidativeeffect once inside the cell [40 41] According to a hypothesis[39] the silencing of the uricase gene with an increase inthe blood level of UA provided an evolutionary advantagefor ancestors of Homo sapiens This hypothesis was based onin vitro experiments which showed that UA is a powerfulscavenger of singlet oxygen peroxyl radicals and hydroxylradicals UA circulating at an elevated level was proposedto be one of the major antioxidants of the plasma thatprotects cells from oxidative damage thereby contributingto an increase in life span of human species and decreasingthe risk of cancer [42] On the other hand a vast literatureon the epidemiology of cardiovascular disease hypertensionand metabolic syndrome overwhelmingly shows that atleast among modern Homo sapiens a high level of UA isstrongly associated with and in many cases predicts devel-opment of hypertension visceral obesity insulin resistancedyslipidemia diabetes kidney disease and cardiovascularand cerebrovascular events [42] Antioxidant effect of UAvaries according to the presence of specific componentsin different physiochemical circumstances and in variouscompartments of the human body UA is an antioxidant onlyin the hydrophilic environment and even in the plasma UAcan prevent lipid peroxidation only as long as ascorbic acidis present [43] Major sites where the antioxidant effects havebeen proposed are the central nervous system [44 45] liver[46] and heart [47]

In OA-induced hyperuricemic rat model hyperuricemiacaused intrarenal oxidative stress increased expression ofNOX-4 subunit of renal NADPH oxidase and angiotensinII and decreased NO bioavailability Hyperuricemic ratsalso showed systemic hypertension renal vasoconstrictionand arteriolopathy Tempol (superoxide scavenger) attenu-ated the adverse effect induced by hyperuricemia despiteequivalent hyperuricemia suggesting that UA might causeoxidative stress [48] In another study hyperuricemic ratstreated with OA showed decreased urinary NO metabolites(NO2

minusNO3

minus) systemic hypertension renal vasoconstric-tion and preglomerular arteriolopathy Chronic administra-tion of L-arginine a substrate for endothelial NO synthaseincreased the urinary excretion ofNO

2

minusNO3

minus andpreservedarteriolar structures probably mediated by the antiprolifer-ative effect of NO on vascular smooth muscle cells sug-gesting the role of endothelial dysfunction as a mediator ofrenal injury induced by hyperuricemia [49] A recent studyreported that UA-induced endothelial dysfunction was asso-ciated with mitochondrial alterations and decreased intra-cellular ATP concentrations [50] An experimental model ofstreptozotocin-induced diabetic rats showed that febuxostatimproved endothelial dysfunction via attenuating oxidativestress by XO inhibition [51]

36 Hyperuricemia and Inflammatory Responses UA inducesinflammatory responses Hyperuricemia-induced inflamma-tory response mediates kidney injury via alteration of vascu-lar and tubular cells in kidney UA has the ability to induce


monocyte chemoattractant protein- (MCP-) 1 in vascularsmooth muscle cells suggesting that it may have a role in thevascular changes associated with hypertension and vasculardisease [52] UA also contributes to kidney damage throughvascular cell proliferation induced by activation of COX-2[29] and increased expression of C-reactive protein (CRP)[53] UA has been known to inhibit renal proximal tubulecell proliferation via activation of NF-120581B and cytoplasmicphospholipase A

2[54] Hyperuricemia also increases extra-

cellular matrix (ECM) synthesis through upregulation oflysyl oxidase (LOX) expression in renal tubular epithelialcells [55] UA contributes to tubulointerstitial inflammationby inducing expression of intracellular adhesion molecule-(ICAM-) 1 in renal tubular epithelial cells [37]

XO has been reported to be upregulated by variousinflammatory stimuli such as lipopolysaccharide (LPS)hypoxia and cytokines [56ndash60] Augmented XO eventuallycauses excess ROS formation leading to tissue damagePharmacological inhibitors of XO such as allopurinol andfebuxostat have been reported to have an anti-inflammatoryeffect in various diseases such as atherosclerosis congestiveheart failure acute lung injury renal interstitial fibrosis andischemia-reperfusion injury [61ndash66] A recent study sug-gested amolecularmechanismunderlying the involvement ofXO in inflammatory pathways and it also suggested that XOmediates LPS-induced phosphorylation of JNK through ROSproduction and MKP-1 inactivation leading to MCP-1 pro-duction in macrophages Febuxostat significantly suppressedLPS-induced MCP-1 production in human macrophages andin vivo in mice [56]

37 Hyperuricemia and Epithelial-Mesenchymal TransitionIn the last decade epithelial-mesenchymal transition (EMT)a process by which fully differentiated epithelial cells losetheir epithelial characteristics and undergo phenotypic con-version to mesenchymal cells has emerged as an importantpathway leading to generation of matrix-producing fibrob-lasts and myofibroblasts in kidney fibrosis In addition tokidney fibrosis EMT has been known to play a pivotal role inembryonic development wound healing tissue regenerationand cancer progression [67 68]

A recent study showed that UA exerted a direct effecton renal tubular cells by inducing EMT [69] OA-inducedhyperuricemic rats showed evidence of EMT before thedevelopment of significant tubulointerstitial fibrosis at 4weeks as indicated by decreased E-cadherin expression andan increased 120572-smooth muscle actin (120572-SMA) Allopurinolsignificantly inhibited UA-induced changes in E-cadherinand 120572-SMA with an amelioration of kidney fibrosis at 6weeks In cultured rat renal tubular epithelial cells (NRKcells) UA induced EMT which was blocked by the organicacid transport inhibitor probenecid UA increased expres-sion of transcriptional factors associated with decreasedsynthesis of E-cadherin UA also increased the degradationof E-cadherin via ubiquitination which is of importancesince downregulation of E-cadherin is considered to be atriggering mechanism for EMT This study suggested thatUA-induced EMT of renal tubular cells might be a novel

mechanism explaining the association of hyperuricemia andrenal progression after taking into account that EMT isan early phenomenon in kidney fibrosis [69ndash71] Furtherresearch is required to assess the role of UA in othermesenchymal cell generation pathways

4 Perspective

Theunderlyingmechanisms bywhichUA could cause kidneyfibrosis have been reported in animal models since 2001 andthere has been a growing interest in this topic and numerousretrospective and prospective observational studies havebeen performed to assess the relationship between UA andCKD The majority of data support the role of UA as a causeor exacerbating factor for kidney fibrosis and progressiveCKD Although over the last several years some clinicalintervention trials including randomized controlled trials(RCTs) have further supported this mechanistic role of UA[72ndash78] clinical evidence demonstrating the beneficial effectof UA lowering therapywith XO inhibitors on renoprotectionand prevention of CKD progression is not certain yet andcannot be easily generalized Most of the clinical studies arelimited by their retrospective study design small sample sizeshort follow-up duration or lack of randomization and noadequately powered RCT has yet demonstrated the beneficialeffect of UA-lowering therapy on renal and cardiovascularoutcomes inCKD [5] Currently there is no published clinicaltrial in which febuxostat was used as a XO inhibitor forevaluating the efficacy of UA reduction on progression ofCKD

With regard to the animal models in this research fieldthe uricase inhibitor OA-induced hyperuricemic rat model[26ndash29] was mainly used during the initial several years andall of the studies used allopurinol as a XO inhibitor There-after the research was performed using animal models ofvarious kidney disease conditions such as CsA nephropathy[36] diabetic nephropathy [38 51] obstructive nephropathy[61] ischemia-reperfusion injury [62] and 56 nephrectomyrat model [34] Further research using diverse animal modelsof CKD [79 80] is essential not only for gaining a betterunderstanding of molecular mechanisms of kidney fibrosisbut also for designing more appropriate clinical studies

Febuxostat a chemically engineered nonpurine selectiveinhibitor of XO received approval in February 2009 from theFood and Drug Administration for the chronic managementof hyperuricemia in patients with gout [81] Although its clin-ical use is increasing febuxostat is still generally consideredas a second-line option for patients with gout who are unableto take allopurinol due to hypersensitivity intolerance renalinsufficiency or lack of efficacy in achieving a target serumUA level of lt60mgdL However recently in basic researchfebuxostat has largely replaced allopurinol as a XO inhibitorand several animal studies have shown various beneficialeffects of febuxostat in reducing inflammation oxidativestress and kidney fibrosis [34 61 62] Febuxostat preventedrenal injury in 56 nephrectomy rats with and withoutcoexisting hyperuricemia [34] But still there is little clinicalexperience and there are no clinical trials with febuxostat


Kidney fibrosis

RAS activation

Endothelial dysfunction

Preglomerulararteriolopathy

Inflammation

Oxidative stress

EMT

uarr Uric acid

darr GFR

Figure 2 Mechanisms by which uric acid may cause kidneyfibrosis based on experimental animal studies EMT epithelial-mesenchymal transition RAS renin-angiotensin system

assessing the efficacy of lowering UA on CKD progressionand it is also more expensive than allopurinol

At present drug therapy for asymptomatic hyperuricemiais not actively recommended and this negative approachis mainly due to the absence of evidence from adequatelypowered RCTs on the causality between hyperuricemia andthe onset or progression of CKD Considering the largesample size required for an adequately powered trial aninternational collaboration is necessary

Current research interests focus on developing new effec-tive antifibrotic drugs to slow progression or even reversechronic kidney injury and several compounds which targetvarious components of the fibrotic pathway from signal-ing molecules that include TGF-120573 phosphatidylinositide-3-kinase and chemokines to microRNAs are undergoingclinical trials [82 83] Although at present UA may be oneof the ignored risk factors for CKD and the clinical use ofUA-lowering drugs which include allopurinol and febuxostatis largely confined to gout management discovering thepotential value of XO inhibitors for preventing kidney fibrosisand CKD progression will provide additional valuable toolsfor managing CKD

5 Conclusion

After taking into account the results of all the importantexperimental studiesmentioned above UA andXOmay con-tribute to kidney fibrosis mainly by inducing inflammationendothelial dysfunction oxidative stress and activation ofRAS (Figure 2) Besides hyperuricemia induces alterationsof renal hemodynamics via afferent arteriolopathy and con-tributes to the onset and progression of kidney fibrosis Manyexperimental studies have shown that XO inhibitors mayprevent kidney damage by lowering UA and inhibiting XOHowever there is no sufficient evidence from interventionalclinical researches supporting the causal relationship betweenUA and kidney fibrosis a final common pathway of CKDprogression Thus the time is not quite appropriate for rec-ommending the widespread clinical use of XO inhibitors forpreventing CKD progression in patients with hyperuricemia

and more so in patients without hyperuricemia The effectand role of XO inhibitors in preventing kidney fibrosis andCKD progression must be further explored by performingfuture large scale clinical trials

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] S B Lee and R Kalluri ldquoMechanistic connection betweeninflammation and fibrosisrdquoKidney International vol 78 no 119pp S22ndashS26 2010

[2] L H Beck ldquoRequiem for gouty nephropathyrdquo Kidney Interna-tional vol 30 no 2 pp 280ndash287 1986

[3] V Filiopoulos D Hadjiyannakos and D Vlassopoulos ldquoNewinsights into uric acid effects on the progression and prognosisof chronic kidney diseaserdquo Renal Failure vol 34 no 4 pp 510ndash520 2012

[4] D-HKang andWChen ldquoUric acid and chronic kidney diseasenew understanding of an old problemrdquo Seminars in Nephrologyvol 31 no 5 pp 447ndash452 2011

[5] S V Badve F Brown C M Hawley et al ldquoChallenges ofconducting a trial of uric-acid-lowering therapy in CKDrdquoNature Reviews Nephrology vol 7 no 5 pp 295ndash300 2011

[6] D I Jalal M Chonchol W Chen and G Targher ldquoUric acidas a target of therapy in CKDrdquoThe American Journal of KidneyDiseases vol 61 no 1 pp 134ndash146 2013

[7] R J Johnson TNakagawa D Jalal L G Sanchez-Lozada DHKang and E Ritz ldquoUric acid and chronic kidney disease whichis chasing whichrdquo Nephrology Dialysis Transplantation vol 28no 9 pp 2221ndash2228 2013

[8] G Bellomo ldquoUric acid and chronic kidney disease a time toactrdquoWorld Journal of Nephrology vol 2 no 2 pp 17ndash25 2013

[9] D Gustafsson and R Unwin ldquoThe pathophysiology of hype-ruricaemia and its possible relationship to cardiovascular dis-ease morbidity and mortalityrdquo BMC Nephrology vol 14 article164 2013

[10] C E Berry and J M Hare ldquoXanthine oxidoreductase andcardiovascular disease molecular mechanisms and pathophys-iological implicationsrdquo Journal of Physiology vol 555 part 3 pp589ndash606 2004

[11] H K Choi D B Mount and A M Reginato ldquoPathogenesis ofgoutrdquo Annals of Internal Medicine vol 143 no 7 pp 499ndash5162005

[12] S Watanabe D-H Kang L Feng et al ldquoUric acid hominoidevolution and the pathogenesis of salt-sensitivityrdquo Hyperten-sion vol 40 no 3 pp 355ndash360 2002

[13] N L Edwards ldquoThe role of hyperuricemia and gout in kid-ney and cardiovascular diseaserdquo Cleveland Clinic Journal ofMedicine vol 75 supplement 5 pp S13ndashS16 2008

[14] D J Levinson and L B Sorensen ldquoRenal handling of uricacid in normal and gouty subjects evidence for a 4-componentsystemrdquoAnnals of the Rheumatic Diseases vol 39 no 2 pp 173ndash179 1980

[15] A Taniguchi and N Kamatani ldquoControl of renal uric acidexcretion and goutrdquo Current Opinion in Rheumatology vol 20no 2 pp 192ndash197 2008


[16] Y Takano K Hase-Aoki H Horiuchi et al ldquoSelectivity offebuxostat a novel non-purine inhibitor of xanthine oxi-dasexanthine dehydrogenaserdquo Life Sciences vol 76 no 16 pp1835ndash1847 2005

[17] T Hosoya K Kimura S Itoh et al ldquoThe effect of febuxostatto prevent a further reduction in renal function of patients withhyperuricemia who have never had gout and are complicated bychronic kidney disease stage 3 study protocol for a multicenterrandomized controlled studyrdquo Trials vol 15 no 1 p 26 2014

[18] B A Grabowski R Khosravan L Vernillet and D J MulfordldquoMetabolism and excretion of [14C] febuxostat a novel non-purine selective inhibitor of xanthine oxidase in healthy malesubjectsrdquo Journal of Clinical Pharmacology vol 51 no 2 pp189ndash201 2011

[19] I Garcia-Valladares T Khan and L R Espinoza ldquoEfficacy andsafety of febuxostat in patients with hyperuricemia and goutrdquoTherapeutic Advances in Musculoskeletal Disease vol 3 no 5pp 245ndash253 2011

[20] K Komoriya S Hoshide K Takeda et al ldquoPharmacokineticsand pharmacodynamics of febuxostat (TMX-67) a non-purineselective inhibitor of xanthine oxidasexanthine dehydrogenase(NPSIXO) in patients with gout andor hyperuricemiardquo Nucle-osides Nucleotides and Nucleic Acids vol 23 no 8-9 pp 1119ndash1122 2004

[21] Y Osada M Tsuchimoto H Fukushima et al ldquoHypouricemiceffect of the novel xanthine oxidase inhibitor TEI-6720 inrodentsrdquo European Journal of Pharmacology vol 241 no 2-3pp 183ndash188 1993

[22] S P Bruce ldquoFebuxostat a selective xanthine oxidase inhibitorfor the treatment of hyperuricemia and goutrdquo Annals of Phar-macotherapy vol 40 no 12 pp 2187ndash2194 2006

[23] C L Gray and N E Walters-Smith ldquoFebuxostat for treatmentof chronic goutrdquo The American Journal of Health-System Phar-macy vol 68 no 5 pp 389ndash398 2011

[24] R J Johnson S D Kivlighn Y-G Kim S Suga and AB Fogo ldquoReappraisal of the pathogenesis and consequencesof hyperuricemia in hypertension cardiovascular disease andrenal diseaserdquoThe American Journal of Kidney Diseases vol 33no 2 pp 225ndash234 1999

[25] X Wu M Wakamiya S Vaishnav et al ldquoHyperuricemia andurate nephropathy in urate oxidase-deficient micerdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 91 no 2 pp 742ndash746 1994

[26] M Mazzali J Hughes Y-G Kim et al ldquoElevated uricacid increases blood pressure in the rat by a novel crystal-independent mechanismrdquoHypertension vol 38 no 5 pp 1101ndash1106 2001

[27] M Mazzali J Kanellis L Han et al ldquoHyperuricemiainduces a primary renal arteriolopathy in rats by a bloodpressure-independent mechanismrdquo The American Journal ofPhysiologymdashRenal Physiology vol 282 no 6 pp F991ndashF9972002

[28] L G Sanchez-Lozada E Tapia J Santamarıa et al ldquoMild hype-ruricemia induces vasoconstriction and maintains glomerularhypertension in normal and remnant kidney ratsrdquo KidneyInternational vol 67 no 1 pp 237ndash247 2005

[29] D-H Kang T Nakagawa L Feng et al ldquoA role for uric acid inthe progression of renal diseaserdquo Journal of the American Societyof Nephrology vol 13 no 12 pp 2888ndash2897 2002

[30] V Diwan A Mistry G Gobe and L Brown ldquoAdenine-inducedchronic kidney and cardiovascular damage in ratsrdquo Journal of

Pharmacological and Toxicological Methods vol 68 no 2 pp197ndash207 2013

[31] M Correa-Costa T T Braga P Semedo et al ldquoPivotal roleof toll-like receptors 2 and 4 its adaptor molecule MyD88and inflammasome complex in experimental tubule-interstitialnephritisrdquo PLoS ONE vol 6 no 12 Article ID e29004 2011

[32] L G Sanchez-Lozada E Tapia V Soto et al ldquoTreatment withthe xanthine oxidase inhibitor febuxostat lowers uric acid andalleviates systemic and glomerular hypertension in experimen-tal hyperuricaemiardquo Nephrology Dialysis Transplantation vol23 no 4 pp 1179ndash1185 2008

[33] L G Sanchez-Lozada E Tapia C Avila-Casado et al ldquoMildhyperuricemia induces glomerular hypertension in normalratsrdquoTheAmerican Journal of PhysiologymdashRenal Physiology vol283 no 5 pp F1105ndashF1110 2002

[34] L G Sanchez-Lozada E Tapia V Soto et al ldquoEffect of febux-ostat on the progression of renal disease in 56 nephrectomyrats with and without hyperuricemiardquo NephronmdashPhysiologyvol 108 no 4 pp p69ndashp78 2008

[35] MMazzali Y-G Kim S-I Suga et al ldquoHyperuricemia exacer-bates chronic cyclosporine nephropathyrdquo Transplantation vol71 no 7 pp 900ndash905 2001

[36] F C Mazali R J Johnson and M Mazzali ldquoUse of uric acid-lowering agents limits experimental cyclosporine nephropathyrdquoNephronmdashExperimental Nephrology vol 120 no 1 pp e12ndashe192012

[37] T Kosugi T Nakayama M Heinig et al ldquoEffect of loweringuric acid on renal disease in the type 2 diabetic dbdb micerdquoThe American Journal of PhysiologymdashRenal Physiology vol 297no 2 pp F481ndashF488 2009

[38] S M Kim Y W Choi H Y Seok et al ldquoReducing serum uricacid attenuates TGF-1205731-induced profibrogenic progression intype 2 diabetic nephropathyrdquo Nephron Experimental Nephrol-ogy vol 121 no 3-4 pp e109ndashe121 2012

[39] B N Ames R Cathcart E Schwiers and P HochsteinldquoUric acid provides an antioxidant defense in humans againstoxidant- and radical-caused aging and cancer a hypothesisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 78 no 11 pp 6858ndash6862 1981

[40] D B Corry P Eslami K Yamamoto M D Nyby H Makinoand M L Tuck ldquoUric acid stimulates vascular smooth musclecell proliferation and oxidative stress via the vascular renin-angiotensin systemrdquo Journal of Hypertension vol 26 no 2 pp269ndash275 2008

[41] Y Y Sautin T Nakagawa S Zharikov and R J John-son ldquoAdverse effects of the classic antioxidant uric acid inadipocytes NADPH oxidase-mediated oxidativenitrosativestressrdquoTheAmerican Journal of PhysiologymdashCell Physiology vol293 no 2 pp C584ndashC596 2007

[42] Y Y Sautin and R J Johnson ldquoUric acid the oxidant-antioxidant paradoxrdquo Nucleosides Nucleotides and NucleicAcids vol 27 no 6-7 pp 608ndash619 2008

[43] B Frei R Stocker and B N Ames ldquoAntioxidant defenses andlipid peroxidation in human blood plasmardquo Proceedings of theNational Academy of Sciences of the United States of Americavol 85 no 24 pp 9748ndash9752 1988

[44] Z F Yu A J Bruce-Keller Y Goodman and M P MattsonldquoUric acid protects neurons against excitotoxic and metabolicinsults in cell culture and against focal ischemic brain injury invivordquo Journal of Neuroscience Research vol 53 no 5 pp 613ndash625 1998


[45] D C Hooper S Spitsin R B Kean et al ldquoUric acid anatural scavenger of peroxynitrite in experimental allergicencephalomyelitis and multiple sclerosisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 95 no 2 pp 675ndash680 1998

[46] K Tsukada T Hasegawa S Tsutsumi et al ldquoEffect of uric acidon liver injury during hemorrhagic shockrdquo Surgery vol 127 no4 pp 439ndash446 2000

[47] B F Becker N Reinholz T Ozcelik B Leipert and E GerlachldquoUric acid as radical scavenger and antioxidant in the heartrdquoPflugers Archiv European Journal of Physiology vol 415 no 2pp 127ndash135 1989

[48] L G Sanchez-Lozada V Soto E Tapia et al ldquoRole of oxidativestress in the renal abnormalities induced by experimentalhyperuricemiardquo The American Journal of PhysiologymdashRenalPhysiology vol 295 no 4 pp F1134ndashF1141 2008

[49] L G Sanchez-Lozada E Tapia R Lopez-Molina et al ldquoEffectsof acute and chronic L-arginine treatment in experimentalhyperuricemiardquo The American Journal of PhysiologymdashRenalPhysiology vol 292 no 4 pp 1238ndash1244 2007

[50] L G Sanchez-Lozada M A Lanaspa M Cristobal-Garcıa etal ldquoUric acid-induced endothelial dysfunction is associatedwith mitochondrial alterations and decreased intracellular ATPconcentrationsrdquoNephron Experimental Nephrology vol 121 no3-4 pp e71ndashe78 2012

[51] S J Hwang K H Lee H H Jang et al ldquoFebuxostat contributesto improvement of endothelial dysfunction in an experimentalmodel of streptozocin-induced diabetic ratsrdquo InternationalJournal of Cardiology vol 171 no 3 pp e110ndashe112 2014

[52] J Kanellis S Watanabe J H Li et al ldquoUric acid stimulatesmonocyte chemoattractant protein-1 production in vascularsmooth muscle cells via mitogen-activated protein kinase andcyclooxygenase-2rdquo Hypertension vol 41 no 6 pp 1287ndash12932003

[53] D-H Kang S-K Park I-K Lee and R J Johnson ldquoUricacid-induced C-reactive protein expression implication on cellproliferation and nitric oxide production of human vascularcellsrdquo Journal of the American Society of Nephrology vol 16 no12 pp 3553ndash3562 2005

[54] H J Han M J Lim Y J Lee J H Lee I S Yang and MTaub ldquoUric acid inhibits renal proximal tubule cell proliferationvia at least two signaling pathways involving PKC MAPKcPLA2 andNF-120581BrdquoTheAmerican Journal of PhysiologymdashRenalPhysiology vol 292 no 1 pp F373ndashF381 2007

[55] Z YangW Xiaohua J Lei et al ldquoUric acid increases fibronectinsynthesis through upregulation of lysyl oxidase expression inrat renal tubular epithelial cellsrdquo The American Journal ofPhysiologymdashRenal Physiology vol 299 no 2 pp F336ndashF3462010

[56] J Nomura N Busso A Ives et al ldquoFebuxostat an inhibitorof xanthine oxidase suppresses lipopolysaccharide-inducedMCP-1 production via MAPK phosphatase-1-mediated inacti-vation of JNKrdquo PLoS ONE vol 8 no 9 Article ID e75527 2013

[57] R P Brandes G Koddenberg W Gwinner et al ldquoRoleof increased production of superoxide anions by NAD(P)Hoxidase and xanthine oxidase in prolonged endotoxemiardquoHypertension vol 33 no 5 pp 1243ndash1249 1999

[58] P M Hassoun F-S Yu C G Cote et al ldquoUpregulationof xanthine oxidase by lipopolysaccharide interleukin-1 andhypoxia role in acute lung injuryrdquo The American Journal ofRespiratory and Critical Care Medicine vol 158 no 1 pp 299ndash305 1998

[59] U S Kayyali C Donaldson H Huang R Abdelnour and PMHassoun ldquoPhosphorylation of xanthine dehydrogenaseoxidasein hypoxiardquo Journal of Biological Chemistry vol 276 no 17 pp14359ndash14365 2001

[60] K Nakai M B Kadiiska J-J Jiang K Stadler and R P MasonldquoFree radical production requires both inducible nitric oxidesynthase and xanthine oxidase in LPS-treated skinrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 103 no 12 pp 4616ndash4621 2006

[61] H Omori N Kawada K Inoue et al ldquoUse of xanthine oxidaseinhibitor febuxostat inhibits renal interstitial inflammation andfibrosis in unilateral ureteral obstructive nephropathyrdquo Clinicaland Experimental Nephrology vol 16 pp 549ndash556 2012

[62] H Tsuda N Kawada J Y Kaimori et al ldquoFebuxostat sup-pressed renal ischemia-reperfusion injury via reduced oxidativestressrdquo Biochemical and Biophysical Research Communicationsvol 427 no 2 pp 266ndash272 2012

[63] A Kushiyama H Okubo H Sakoda et al ldquoXanthine oxidore-ductase is involved in macrophage foam cell formation andatherosclerosis developmentrdquo Arteriosclerosis Thrombosis andVascular Biology vol 32 no 2 pp 291ndash298 2012

[64] K Schroder C Vecchione O Jung et al ldquoXanthine oxidaseinhibitor tungsten prevents the development of atherosclerosisin ApoE knockout mice fed a Western-type dietrdquo Free RadicalBiology and Medicine vol 41 no 9 pp 1353ndash1360 2006

[65] N Engberding S Spiekermann A Schaefer et al ldquoAllopurinolattenuates left ventricular remodeling and dysfunction afterexperimental myocardial infarction a new action for an olddrugrdquo Circulation vol 110 no 15 pp 2175ndash2179 2004

[66] R M Wright L A Ginger N Kosila et al ldquoMononuclearphagocyte xanthine oxidoreductase contributes to cytokine-induced acute lung injuryrdquoThe American Journal of RespiratoryCell and Molecular Biology vol 30 no 4 pp 479ndash490 2004

[67] Y Liu ldquoNew insights into epithelial-mesenchymal transition inkidney fibrosisrdquo Journal of the American Society of Nephrologyvol 21 no 2 pp 212ndash222 2010

[68] R M Carew B Wang and P Kantharidis ldquoThe role of EMT inrenal fibrosisrdquo Cell and Tissue Research vol 347 no 1 pp 103ndash116 2012

[69] E S Ryu M J Kim H S Shin et al ldquoUric acid-induced phe-notypic transition of renal tubular cells as a novel mechanism ofchronic kidney diseaserdquo The American Journal of PhysiologymdashRenal Physiology vol 304 no 5 pp F471ndashF480 2013

[70] R Kalluri ldquoEMT when epithelial cells decide to becomemesenchymal-like cellsrdquo Journal of Clinical Investigation vol119 no 6 pp 1417ndash1419 2009

[71] R Kalluri and E G Neilson ldquoEpithelial-mesenchymal tran-sition and its implications for fibrosisrdquo Journal of ClinicalInvestigation vol 112 no 12 pp 1776ndash1784 2003

[72] D A J Neal B D M Tom A E S Gimson P Gibbs and GJ M Alexander ldquoHyperuricemia gout and renal function afterliver transplantationrdquo Transplantation vol 72 no 10 pp 1689ndash1691 2001

[73] L D Fairbanks J S Cameron G Venkat-Raman et al ldquoEarlytreatment with allopurinol in familial juvenil hyerpuricaemicnephropathy (FJHN) ameliorates the long-term progressionof renal diseaserdquo QJMmdashMonthly Journal of the Association ofPhysicians vol 95 no 9 pp 597ndash607 2002

[74] Y-P Siu K-T Leung M K-H Tong and T-H Kwan ldquoUse ofallopurinol in slowing the progression of renal disease throughits ability to lower serum uric acid levelrdquoThe American Journalof Kidney Diseases vol 47 no 1 pp 51ndash59 2006


[75] M Kanbay A Ozkara Y Selcoki et al ldquoEffect of treatment ofhyperuricemia with allopurinol on blood pressure creatinineclearence and proteinuria in patients with normal renal func-tionsrdquo International Urology and Nephrology vol 39 no 4 pp1227ndash1233 2007

[76] M Kanbay B Afsar and A Covic ldquoUric acid as a car-diometabolic risk factor to be or not to berdquo Contributions toNephrology vol 171 pp 62ndash67 2011

[77] M Goicoechea S G de Vinuesa U Verdalles et al ldquoEffectof allopurinol in chronic kidney disease progression and car-diovascular riskrdquo Clinical Journal of the American Society ofNephrology vol 5 no 8 pp 1388ndash1393 2010

[78] B H Pai G Swarnalatha R Ram and K V DakshinamurtyldquoAllopurinol for prevention of progression of kidney diseasewith hyperuricemiardquo Indian Journal of Nephrology vol 23 no4 pp 280ndash286 2013

[79] H-C Yang Y Zuo and A B Fogo ldquoModels of chronic kidneydiseaserdquo Drug Discovery Today Disease Models vol 7 no 1-2pp 13ndash19 2010

[80] G J Becker and T D Hewitson ldquoAnimal models of chronickidney disease useful but not perfectrdquo Nephrology DialysisTransplantation vol 28 no 10 pp 2432ndash2438 2013

[81] ldquoFebuxostat (Uloric) for chronic treatment of goutrdquoTheMedicalletter on drugs and therapeutics vol 51 no 1312 pp 37ndash38 2009

[82] D Tampe and M Zeisberg ldquoPotential approaches to reverse orrepair renal fibrosisrdquo Nature Reviews Nephrology vol 10 no 4pp 226ndash237 2014

[83] S P Srivastava D Koya and K Kanasaki ldquoMicroRNAs inkidney fibrosis and diabetic nephropathy roles on EMT andEndMTrdquo BioMed Research International vol 2013 Article ID125469 10 pages 2013

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


AMP IMP

Adenosine Inosine

Hypoxanthine

GMP

Guanosine

Guanine

Xanthine Uric acid

MSU

Xanthine oxidase

Xanthine oxidase

Allopurinolfebuxostat

1 11

2

3

4

4

5H O2 2 H O2 2H2O2 O2

H2O2 O2

Figure 1 The pathway of purine nucleotides degradation in humans showing the competitive inhibition of uric acid formation by xanthineoxidase inhibitors and the site of action AMP adenosine monophosphate GMP guanosine monophosphate IMP inosine monophosphateMSU monosodium urate A 51015840-nucleotidase B AMP deaminase C adenosine deaminase D purine nucleoside phosphorylase Eguanine deaminase

2 Physiopathology of Uric Acid

Cell turnover leads to the production of adenosine inosineand guanosine They degrade to hypoxanthine and xanthinewhich are the substrates for the widely distributed XO inthe formation of UA XO catalyzes the oxidation of purinesubstrates xanthine and hypoxanthine producing both UAand reactive oxygen species (ROS) Thus XO is one of themajor enzymatic sources of ROS Allopurinol and febuxostatare inhibitors of XO and they reduce uric acid and ROSformation (Figure 1) [10]

UA is the oxidation end-product of purine metabolism inhumans and higher primates Most other mammals exceptfor the Dalmatian dogs can degrade UA further to water-soluble allantoin with the enzyme uricase and as a resultserum urate levels are about 10 of those in humans [9 11]However in humans and higher primates mutations in theuricase gene occurred during evolution and making theenzyme nonfunctional resulted in higher levels of serumUAthan in other mammals [12]

Urates are the ionized form of UA and at a physiologicpH of 74 over 95 of UA dissociates into urates with98 existing as monosodium urate The serum urate leveldepends on dietary purines the breakdown of endogenouspurines and the renal and intestinal excretion of urateHyperuricemia is defined as the accumulation of serumUA beyond its solubility point in water (68mgdL) andit develops due to UA overproduction undersecretion orboth [13] The dominating factor contributing to hyper-uricemia is underexcretion of urate [11] Under normalconditions 70 of the UA produced is eliminated in theurine and the remaining UA is removed via biliary secretion

In the kidney urate is easily filtered through the glomerulusand subsequently reabsorbed by the proximal tubule cells ofthe kidney and after further absorption about 10 of urateis finally excreted [14] An anion exchanger and a voltage-dependent pathway seem to be the mechanisms involved inurate transport [15]

Allopurinol a purine inhibitor of XO has been con-ventionally used for urate-lowering therapy to inhibit UAsynthesis A novel urate-lowering drug febuxostat is a potentnonpurine selective inhibitor of XO and it inhibits both thereduced and oxidized forms of the enzyme in contrast toallopurinol that inhibits the reduced form of the enzyme only[16 17] Febuxostat is metabolizedmainly by glucuronidationand oxidation in the liver has its dual (urinary and fecal)pathways in excretion (urinary and fecal excretion rates491 and 449 resp) and is effective and well tolerated inpatients withmild tomoderate renal and hepatic impairment[18 19] Animal studies have demonstrated that febuxostathas a greater UA-lowering effect than allopurinol [20 21]Febuxostatrsquos chemical structure does not resemble a pyrim-idine or purine and is unlike that of allopurinol [22] It doesnot inhibit other enzymes involved in purine or pyrimidinemetabolism [23]

Studying the role ofUA in kidney fibrosis a processwhicheventually leads to CKD is very difficult since uric acid isexcreted primarily by the kidney and hence a decrease in theglomerular filtration rate (GFR) is inevitably accompanied bya rise in the serumUA level As such studies in experimentalanimals in which serum UA can be modulated are critical tounderstand whether there is a role for UA in the causation orprogression of CKD [7]















minusNO3


2

minusNO3











4 Perspective





Kidney fibrosis

RAS activation



Inflammation

Oxidative stress

EMT

uarr Uric acid

darr GFR





5 Conclusion





References





























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























minusNO3


2

minusNO3











4 Perspective





Kidney fibrosis

RAS activation



Inflammation

Oxidative stress

EMT

uarr Uric acid

darr GFR





5 Conclusion





References





























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























4 Perspective





Kidney fibrosis

RAS activation



Inflammation

Oxidative stress

EMT

uarr Uric acid

darr GFR





5 Conclusion





References





























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Kidney fibrosis

RAS activation



Inflammation

Oxidative stress

EMT

uarr Uric acid

darr GFR





5 Conclusion





References





























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article the role of uric acid in kidney fibrosis ...another animal model of...

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