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American Journal of Kidney Diseases

Uric Acid as a Target of Therapy in CKD

Published:October 11, 2012DOI:https://doi.org/10.1053/j.ajkd.2012.07.021
      The prevalence of chronic kidney disease (CKD) has increased and will continue to increase in the United States and worldwide. This is alarming considering that CKD is an irreversible condition and patients who progress to chronic kidney failure have reduced quality of life and high mortality rates. As such, it is imperative to identify modifiable risk factors to develop strategies to slow CKD progression. One such factor is hyperuricemia. Recent observational studies have associated hyperuricemia with kidney disease. In addition, hyperuricemia is largely prevalent in patients with CKD. Data from experimental studies have shown several potential mechanisms by which hyperuricemia may contribute to the development and progression of CKD. In this article, we offer a critical review of the experimental evidence linking hyperuricemia to CKD, highlight gaps in our knowledge on the topic as it stands today, and review the observational and interventional studies that have examined the potential nephroprotective effect of decreasing uric acid levels in patients with CKD. Although uric acid also may be linked to cardiovascular disease and mortality in patients with CKD, this review focuses only on uric acid as a potential therapeutic target to prevent kidney disease onset and progression.

      Index Words

      In the last few decades, chronic kidney disease (CKD) has emerged as a global health problem of epidemic proportions.
      • Levey A.S.
      • Atkins R.
      • Coresh J.
      • et al.
      Chronic kidney disease as a global public health problem: approaches and initiatives—a position statement from Kidney Disease Improving Global Outcomes.
      The prevalence of stage 3 CKD has increased in the United States, with current estimates placing it at 11.5%.
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      • Stevens L.A.
      • Schmid C.H.
      • et al.
      A new equation to estimate glomerular filtration rate.
      Although in many persons CKD remains an asymptomatic pathologic condition that progresses slowly, for many others, CKD represents a progressive irreversible process that ultimately requires renal replacement therapy.
      • Fried L.F.
      Higher incidence of ESRD than mortality in the AASK study.
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      • Stevens L.A.
      • Coresh J.
      Conceptual model of CKD: applications and implications.
      • Eijkelkamp W.B.
      • Zhang Z.
      • Remuzzi G.
      • et al.
      Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) trial.
      In addition to the decreased quality of life, mortality rates in patients with end-stage renal disease are extremely high. For example, in the 2011 US Renal Data System report, adjusted mortality rates for maintenance dialysis patients aged 45-64 and 65 years and older were 154 and 313 deaths/1,000 patient-years at risk, respectively. Both rates are 7 times greater than those seen in their counterparts in the general population.
      US Renal Data System
      USRDS 2011 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States.
      Hence, and in the absence of curative therapy for patients with progressive CKD, it is important to pursue therapeutic interventions that may effectively slow CKD progression.
      Carl Wilhelm Scheele, a Swedish pharmacist, discovered uric acid in 1776 in a bladder calculus and named it “acid of calculus.” When the stone was moistened with nitric acid and dried, Scheele noted that the addition of dilute ammonium hydroxide converted it to the purple-red color characteristic of the ammonium salt of purpuric acid.
      • Rosenfeld L.
      Four Centuries of Clinical Chemistry.
      Subsequently, Antoine Francois de Fourcroy, a French chemist, observed that chlorine water changed uric acid to urea and distilling uric acid produced hydrocyanic acid, prompting him to name it “acid urique.”
      • McCrudden F.
      Uric Acid: The Chemistry, Physiology, and Pathology of Uric Acid and the Physiologically Important Purine Bodies, With a Discussion of the Metabolism in Gout.
      Uric acid was thought to have a role in human diseases other than kidney stones as early as 1848, when Alfred Baring Garrod, an English physician, discovered that uric acid is present in the blood of individuals with an acute gout attack; this observation prompted him to conclude that uric acid has a role in gout.
      • McCrudden F.
      Uric Acid: The Chemistry, Physiology, and Pathology of Uric Acid and the Physiologically Important Purine Bodies, With a Discussion of the Metabolism in Gout.
      At the time, skepticism regarding a role for hyperuricemia in gout was roused by subsequent studies in which injecting uric acid into healthy animals and humans failed to induce gout. The skepticism was fueled further by studies showing that uric acid was present in the blood of patients with other diseases, such as leukemia, and did not inevitably lead to the development of gout.
      • Croftan A.
      Uric acid theories.
      Today, although we recognize that hyperuricemia alone is insufficient to cause gout and that other factors likely predispose to crystal formation, we also acknowledge that decreasing uric acid levels is an effective strategy to prevent gout attacks.
      • Shoji A.
      • Yamanaka H.
      • Kamatani N.
      A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy.
      In contrast to gout, and although the association between uric acid, gout, and kidney disease had been noted early on, a role for uric acid–lowering therapies in preventing and slowing kidney disease progression has not been established.

      Uric Acid Homeostasis

      Uric acid is an end product of purine metabolism that is produced mainly by the liver and intestines, but also by other peripheral tissues, such as muscles, the endothelium, and the kidneys. Under normal conditions, two-thirds of the uric acid produced is eliminated in the urine and one-third is removed by the biliary tree. Although uric acid occurs predominantly as a urate anion under physiologic pH, more uric acid than urate is present in urine (pH 5-6).
      • Wright A.F.
      • Rudan I.
      • Hastie N.D.
      • Campbell H.
      A 'complexity' of urate transporters.
      In the kidney, urate is filtered readily by the glomerulus and subsequently reabsorbed by the proximal tubular cells of the kidney; normal fractional excretion of uric acid is ∼10%.
      • Edwards N.L.
      The role of hyperuricemia and gout in kidney and cardiovascular disease.
      The cell membrane is impermeable to the urate anion in the absence of specific transporters. Although urate transport is a complex and incompletely understood process,
      • Wright A.F.
      • Rudan I.
      • Hastie N.D.
      • Campbell H.
      A 'complexity' of urate transporters.
      the efficiency with which the human kidney reabsorbs urate may contribute to the higher serum uric acid levels in humans compared with other species; this in addition to an uricase mutation preventing further uric acid degradation in humans.
      • Alvarez-Lario B.
      • Macarron-Vicente J.
      Uric acid and evolution.
      It generally is accepted that the human urate transporter, URAT1 (encoded by the SLC22A12 gene), facilitates uric acid reabsorption in the proximal convoluted tubule.
      • Enomoto A.
      • Kimura H.
      • Chairoungdua A.
      • et al.
      Molecular identification of a renal urate anion exchanger that regulates blood urate levels.
      More recently, GLUT9 (encoded by SLC2A9), a member of the glucose transporter family, has been proposed to be a major regulator of uric acid homeostasis.
      • Preitner F.
      • Bonny O.
      • Laverriere A.
      • et al.
      Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy.
      In humans, it is expressed mainly in the proximal convoluted tubule on the basolateral membrane.
      • Wright A.F.
      • Rudan I.
      • Hastie N.D.
      • Campbell H.
      A 'complexity' of urate transporters.
      Hyperuricemia is defined as the accumulation of serum uric acid beyond its solubility point in water (6.8 mg/dL) and develops due to uric acid overproduction, undersecretion, or both.
      • Edwards N.L.
      The role of hyperuricemia and gout in kidney and cardiovascular disease.
      Uric acid homeostasis and the main factors that lead to increased serum uric acid levels in CKD are schematically shown in Fig 1.
      Figure thumbnail gr1
      Figure 1Schematic representation of uric acid homeostasis. Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate.

      A Plausible Role for Uric Acid in Kidney Disease

      Traditionally, hyperuricemia associated with hyperuricosuria has been postulated to cause kidney disease by depositing intraluminal crystal in the collecting duct of the nephron in a manner reminiscent of gouty arthropathy.
      • Waisman J.
      • Mwasi L.M.
      • Bluestone R.
      • Klinenberg J.R.
      Acute hyperuricemic nephropathy in rats An electron microscopic study.
      • Spencer H.W.
      • Yarger W.E.
      • Robinson R.R.
      Alterations of renal function during dietary-induced hyperuricemia in the rat.
      Individuals with increased serum uric acid levels secondary to high dietary purine intake also may have lower than normal urinary pH, favoring even more uric acid in urine than urate. Considering that uric acid is less soluble than urate, this milieu would favor uric acid crystal formation.
      • Coe F.L.
      Uric acid and calcium oxalate nephrolithiasis.
      Uric acid crystals have the capacity to adhere to the surface of renal epithelial cells
      • Koka R.M.
      • Huang E.
      • Lieske J.C.
      Adhesion of uric acid crystals to the surface of renal epithelial cells.
      and induce an acute inflammatory response in such cell lines.
      • Umekawa T.
      • Chegini N.
      • Khan S.R.
      Increased expression of monocyte chemoattractant protein-1 (MCP-1) by renal epithelial cells in culture on exposure to calcium oxalate, phosphate and uric acid crystals.
      In addition to an increased risk of kidney stone formation, such effects have been shown to reduce glomerular filtration rate (GFR).
      • Spencer H.W.
      • Yarger W.E.
      • Robinson R.R.
      Alterations of renal function during dietary-induced hyperuricemia in the rat.
      Contrary to the role of uric acid crystals in kidney disease, noncrystal effects of uric acid remain contentious because under physiologic concentrations, urate is a powerful antioxidant that can scavenge superoxide, hydroxyl radicals, and singlet oxygen.
      • Ames B.N.
      • Cathcart R.
      • Schwiers E.
      • Hochstein P.
      Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis.
      Nevertheless, recent data may implicate mild hyperuricemia in kidney disease onset and progression. Experimentally induced hyperuricemia in rats leads to reduced urinary nitrite levels and systemic and glomerular hypertension.
      • Mazzali M.
      • Hughes J.
      • Kim Y.G.
      • et al.
      Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism.
      • Sanchez-Lozada L.G.
      • Tapia E.
      • Lopez-Molina R.
      • et al.
      Effects of acute and chronic l-arginine treatment in experimental hyperuricemia.
      The latter 2 can be prevented with supplementation of l-arginine, suggesting that uric acid may cause endothelial dysfunction. This conclusion, although controversial, is supported by in vitro experimental studies showing that uric acid decreases nitric oxide production
      • Zharikov S.
      • Krotova K.
      • Hu H.
      • et al.
      Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells.
      and also may lead to nitric oxide depletion.
      • Gersch C.
      • Palii S.P.
      • Kim K.M.
      • Angerhofer A.
      • Johnson R.J.
      • Henderson G.N.
      Inactivation of nitric oxide by uric acid.
      In addition to a potential role in endothelial dysfunction, experimental hyperuricemia has been reported to cause an afferent renal arteriolopathy and tubulointerstitial fibrosis in the kidney by activating the renin-angiotensin-aldosterone system.
      • Mazzali M.
      • Kanellis J.
      • Han L.
      • et al.
      Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism.
      Uric acid also has been shown to activate the cytoplasmic phospholipase A2 and inflammatory transcription factor nuclear factor-κB (NF-κB), leading to the inhibition of proximal tubular cellular proliferation in vitro.
      • Han H.J.
      • Lim M.J.
      • Lee Y.J.
      • Lee J.H.
      • Yang I.S.
      • Taub M.
      Uric acid inhibits renal proximal tubule cell proliferation via at least two signaling pathways involving PKC, MAPK, cPLA2, and NF-kappaB.
      Other reported sequelae of increasing serum uric acid levels include systemic cytokine production, such as tumor necrosis factor α,
      • Netea M.G.
      • Kullberg B.J.
      • Blok W.L.
      • Netea R.T.
      • van der Meer J.W.
      The role of hyperuricemia in the increased cytokine production after lipopolysaccharide challenge in neutropenic mice.
      and the local expression of chemokines, such as monocyte chemotactic protein 1 in the kidney
      • Roncal C.A.
      • Mu W.
      • Croker B.
      • et al.
      Effect of elevated serum uric acid on cisplatin-induced acute renal failure.
      • Kang D.H.
      • Nakagawa T.
      • Feng L.
      • et al.
      A role for uric acid in the progression of renal disease.
      and cyclooxygenase 2 (COX-2) in blood vessels.
      • Kang D.H.
      • Nakagawa T.
      • Feng L.
      • et al.
      A role for uric acid in the progression of renal disease.
      Consistent with such experimental data, further animal studies suggest that decreasing uric acid levels may slow CKD progression. Notably, decreasing uric acid levels has been reported to decrease tubulointerstitial fibrosis in both the 5/6 nephrectomy model
      • Sanchez-Lozada L.G.
      • Tapia E.
      • Soto V.
      • et al.
      Effect of febuxostat on the progression of renal disease in 5/6 nephrectomy rats with and without hyperuricemia.
      and diabetic nephropathy.
      • Kosugi T.
      • Nakayama T.
      • Heinig M.
      • et al.
      The effect of lowering uric acid on renal disease in the type 2 diabetic db/db mice.
      Additionally, in humans, withdrawing uric acid–lowering therapy was found to increase urinary transforming growth factor β1 in a group of hyperuricemic patients with CKD.
      • Talaat K.M.
      • el-Sheikh A.R.
      The effect of mild hyperuricemia on urinary transforming growth factor beta and the progression of chronic kidney disease.
      The putative mechanisms by which increased serum uric acid level may contribute to CKD onset and progression are shown in Fig 2.
      Figure thumbnail gr2
      Figure 2Putative mechanisms by which elevated serum uric acid level may contribute to chronic kidney disease (CKD) development and progression. Abbreviations: GFR, glomerular filtration rate; MCP-1, monocyte chemotactic protein 1; NF-KB, nuclear factor-κB; NO, nitric oxide.

      Uric Acid as a Predictor of Human Kidney Disease

      In the last 2 decades, a large number of observational studies have examined the potential link between increased serum uric acid levels and CKD.
      • Domrongkitchaiporn S.
      • Sritara P.
      • Kitiyakara C.
      • et al.
      Risk factors for development of decreased kidney function in a southeast Asian population: a 12-year cohort study.
      • Weiner D.E.
      • Tighiouart H.
      • Elsayed E.F.
      • Griffith J.L.
      • Salem D.N.
      • Levey A.S.
      Uric acid and incident kidney disease in the community.
      • Obermayr R.P.
      • Temml C.
      • Gutjahr G.
      • Knechtelsdorfer M.
      • Oberbauer R.
      • Klauser-Braun R.
      Elevated uric acid increases the risk for kidney disease.
      • Sonoda H.
      • Takase H.
      • Dohi Y.
      • Kimura G.
      Uric acid levels predict future development of chronic kidney disease.
      • Wang S.
      • Shu Z.
      • Tao Q.
      • Yu C.
      • Zhan S.
      • Li L.
      Uric acid and incident chronic kidney disease in a large health check-up population in Taiwan.
      • Mok Y.
      • Lee S.J.
      • Kim M.S.
      • Cui W.
      • Moon Y.M.
      • Jee S.H.
      Serum uric acid and chronic kidney disease: the Severance cohort study.
      • Hovind P.
      • Rossing P.
      • Tarnow L.
      • Johnson R.J.
      • Parving H.H.
      Serum uric acid as a predictor for development of diabetic nephropathy in type 1 diabetes—an inception cohort study.
      • Jalal D.I.
      • Rivard C.J.
      • Johnson R.J.
      • et al.
      Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: findings from the Coronary Artery Calcification in Type 1 Diabetes Study.
      • Ficociello L.H.
      • Rosolowsky E.T.
      • Niewczas M.A.
      • et al.
      High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up.
      • Zoppini G.
      • Targher G.
      • Chonchol M.
      • et al.
      Serum uric acid levels and incident chronic kidney disease in patients with type 2 diabetes and preserved kidney function.
      • Yen C.J.
      • Chiang C.K.
      • Ho L.C.
      • et al.
      Hyperuricemia associated with rapid renal function decline in elderly Taiwanese subjects.
      • Chonchol M.
      • Shlipak M.G.
      • Katz R.
      • et al.
      Relationship of uric acid with progression of kidney disease.
      • Iseki K.
      • Ikemiya Y.
      • Inoue T.
      • Iseki C.
      • Kinjo K.
      • Takishita S.
      Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort.
      • Hsu C.Y.
      • Iribarren C.
      • McCulloch C.E.
      • Darbinian J.
      • Go A.S.
      Risk factors for end-stage renal disease: 25-year follow-up.
      • Bellomo G.
      • Venanzi S.
      • Verdura C.
      • Saronio P.
      • Esposito A.
      • Timio M.
      Association of uric acid with change in kidney function in healthy normotensive individuals.
      • Ben-Dov I.Z.
      • Kark J.D.
      Serum uric acid is a GFR-independent long-term predictor of acute and chronic renal insufficiency: the Jerusalem Lipid Research Clinic cohort study.
      • Sturm G.
      • Kollerits B.
      • Neyer U.
      • Ritz E.
      • Kronenberg F.
      Uric acid as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study.
      • Madero M.
      • Sarnak M.J.
      • Wang X.
      • et al.
      Uric acid and long-term outcomes in CKD.
      • Iseki K.
      • Oshiro S.
      • Tozawa M.
      • Iseki C.
      • Ikemiya Y.
      • Takishita S.
      Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects.
      • Kuo C.F.
      • Luo S.F.
      • See L.C.
      • et al.
      Hyperuricaemia and accelerated reduction in renal function.
      • Altemtam N.
      • Russell J.
      • El Nahas M.
      A study of the natural history of diabetic kidney disease (DKD).
      • Ishani A.
      • Grandits G.A.
      • Grimm R.H.
      • et al.
      Association of single measurements of dipstick proteinuria, estimated glomerular filtration rate, and hematocrit with 25-year incidence of end-stage renal disease in the Multiple Risk Factor Intervention Trial.
      • Syrjanen J.
      • Mustonen J.
      • Pasternack A.
      Hypertriglyceridaemia and hyperuricaemia are risk factors for progression of IgA nephropathy.
      • Ohno I.
      • Hosoya T.
      • Gomi H.
      • Ichida K.
      • Okabe H.
      • Hikita M.
      Serum uric acid and renal prognosis in patients with IgA nephropathy.
      These studies (summarized in Table 1) have shown conflicted results in some instances. For example, an analysis of the Cardiovascular Health Study (CHS),
      • Chonchol M.
      • Shlipak M.G.
      • Katz R.
      • et al.
      Relationship of uric acid with progression of kidney disease.
      which involved 5,808 participants with 5 years of follow-up, showed no significant association between serum uric acid level and incident CKD, and yet there was a significant relationship between increased serum uric acid level and CKD progression even after adjustment for age, sex, race, serum creatinine level, body mass index, waist circumference, blood pressure, use of antihypertensive drugs, use of allopurinol, blood glucose level, lipid levels, ankle-arm index, carotid intima-media thickness, major electrocardiogram abnormalities, hemoglobin level, C-reactive protein level, and albumin level. However, the older age of this population may have precluded the identification of serum uric acid level as a predictor of incident CKD. Consistent with this, serum uric acid level was found to be an independent risk factor for incident CKD in a pooled analysis of the Atherosclerosis Risk in Communities (ARIC) Study and the CHS. This analysis involved 13,338 participants with intact kidney function at baseline who were followed for a mean of 8.5 years.
      • Weiner D.E.
      • Tighiouart H.
      • Elsayed E.F.
      • Griffith J.L.
      • Salem D.N.
      • Levey A.S.
      Uric acid and incident kidney disease in the community.
      Similar findings were reported from the Vienna Health Screening Project, in which an analysis of 21,475 healthy participants followed up for 7 years indicated that elevated baseline uric acid levels were associated with increased risk of incident CKD (defined as GFR <60 mL/min/1.73 m2) independently of age, sex, waist circumference, plasma lipid levels, fasting plasma glucose level, estimated GFR, blood pressure, and use of antihypertensive drugs.
      • Obermayr R.P.
      • Temml C.
      • Gutjahr G.
      • Knechtelsdorfer M.
      • Oberbauer R.
      • Klauser-Braun R.
      Elevated uric acid increases the risk for kidney disease.
      Such an independent association between serum uric acid level and incident CKD also has been corroborated by many other studies of Asian populations.
      • Domrongkitchaiporn S.
      • Sritara P.
      • Kitiyakara C.
      • et al.
      Risk factors for development of decreased kidney function in a southeast Asian population: a 12-year cohort study.
      • Sonoda H.
      • Takase H.
      • Dohi Y.
      • Kimura G.
      Uric acid levels predict future development of chronic kidney disease.
      • Wang S.
      • Shu Z.
      • Tao Q.
      • Yu C.
      • Zhan S.
      • Li L.
      Uric acid and incident chronic kidney disease in a large health check-up population in Taiwan.
      • Mok Y.
      • Lee S.J.
      • Kim M.S.
      • Cui W.
      • Moon Y.M.
      • Jee S.H.
      Serum uric acid and chronic kidney disease: the Severance cohort study.
      In addition, elevated serum uric acid levels appear to be associated with increased risk of diabetic nephropathy in both type 1 and 2 diabetes.
      • Jalal D.I.
      • Rivard C.J.
      • Johnson R.J.
      • et al.
      Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: findings from the Coronary Artery Calcification in Type 1 Diabetes Study.
      • Ficociello L.H.
      • Rosolowsky E.T.
      • Niewczas M.A.
      • et al.
      High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up.
      • Zoppini G.
      • Targher G.
      • Chonchol M.
      • et al.
      Serum uric acid levels and incident chronic kidney disease in patients with type 2 diabetes and preserved kidney function.
      Table 1Main Prospective Studies of the Association Between Elevated Serum Uric Acid Level and CKD Development or Progression
      StudyStudy Population (N)F/U (y)Independent VariableStudy OutcomeAdjustments ConsideredFindings
      Iseki et al
      • Iseki K.
      • Oshiro S.
      • Tozawa M.
      • Iseki C.
      • Ikemiya Y.
      • Takishita S.
      Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects.
      Okinawa General Health Maintenance Association (6,403)2Hyperuricemia (≥8 mg/dL)Incident CKD (SCr ≥1.4 [♂] or ≥1.2 [♀])Age, sex, BMI, SBP, fasting glucose, sAlb, total cholesterol, proteinuria, hematuria, smoking, alcohol intake, physical activityHyperuricemia independently associated with risk of developing higher SCr; aHR, 2.91 (1.8-4.7) in ♂, 10.4 (1.9-56.6) in ♀
      Domrongkitchaiporn et al
      • Domrongkitchaiporn S.
      • Sritara P.
      • Kitiyakara C.
      • et al.
      Risk factors for development of decreased kidney function in a southeast Asian population: a 12-year cohort study.
      Employees of the Electric Generation Authority of Thailand (3,499)12Hyperuricemia (≥6.3 mg/dL)Incident CKD (eGFR <60)BMI, SBP, DBP, DM status, proteinuria, serum cholesterol, smoking historyHyperuricemia independently associated with increased risk of incident CKD: aOR, 1.82 (1.12-2.98)
      Weiner et al
      • Weiner D.E.
      • Tighiouart H.
      • Elsayed E.F.
      • Griffith J.L.
      • Salem D.N.
      • Levey A.S.
      Uric acid and incident kidney disease in the community.
      ARIC and CHS (13,338)8.5Serum uric acid levels (per 1-mg/dL increase)Incident CKD (eGFR decrease ≥15 with final eGFR <60 or SCr increase ≥0.4 with final SCr >1.4 [♂] or ≥1.2 [♀])Age, sex, race, DM status, SBP, HTN status, CVD, LVH, smoking, alcohol use, education, total cholesterol, HDL-C, sAlb, Hct, baseline kidney functionSerum uric acid independently associated with increased risk of incident CKD: aOR, 1.07 (1.01-1.14)
      Obermayr et al
      • Obermayr R.P.
      • Temml C.
      • Gutjahr G.
      • Knechtelsdorfer M.
      • Oberbauer R.
      • Klauser-Braun R.
      Elevated uric acid increases the risk for kidney disease.
      The Vienna Health Screening Project (21,475)7Hyperuricemia (moderate [7-8.9 mg/dL] and significant [≥9 mg/dL])Incident CKD (eGFR <60)Age, sex, waist circumference, HDL-C, blood glucose, triglycerides, eGFR, mean BP, HTN medicationsModerately elevated serum uric acid independently associated with increased risk of incident CKD: aOR, 1.26 (1.02-1.55); for significantly elevated serum uric acid: aOR, 1.63 (1.18-2.27)
      Sonoda et al
      • Sonoda H.
      • Takase H.
      • Dohi Y.
      • Kimura G.
      Uric acid levels predict future development of chronic kidney disease.
      Health checkup screening of non-DM healthy people (7,078)4.5Uric acid level (per 1-mg/dL increase)Incident CKD (eGFR <60)BMI, smoking, SBP, fasting glucose, LDL-C, HDL-C, Hb, eGFR, smokingSerum uric acid an independent predictor of incident CKD: aOR, 1.09 (1.01-1.18); P = 0.03
      Wang et al
      • Wang S.
      • Shu Z.
      • Tao Q.
      • Yu C.
      • Zhan S.
      • Li L.
      Uric acid and incident chronic kidney disease in a large health check-up population in Taiwan.
      Retrospective cohort study of Taiwanese adults (94,422)3.5Hyperuricemia (≥7.3 mg/dL)Incident CKD (eGFR <60)Age, sex, education status, alcohol intake, smoking, HTN, DM status, physical activity, BMI, lipid profile, sAlb, Hb, CRP, GGT, SUN, eGFR, proteinuria, hematuria, medication use
      Allopurinol, lipid-lowering drug, Chinese herbal medicine.
      Hyperuricemia independently associated with increased risk of incident CKD: aHR, 1.15 (1.01-1.30); P < 0.05
      Mok et al
      • Mok Y.
      • Lee S.J.
      • Kim M.S.
      • Cui W.
      • Moon Y.M.
      • Jee S.H.
      Serum uric acid and chronic kidney disease: the Severance cohort study.
      The Severance cohort study in Korea (14,939)10.2Hyperuricemia (≥6.6 mg/dL [♂] or ≥4.6 mg/dL [♀])Incident CKD (eGFR <60)Age, smoking, alcohol consumption, physical activity, BMI, total cholesterol, HTN status, DMIncreased risk of incident CKD with hyperuricemia: aHR, 2.1 (1.6-2.9) in ♂ (P < 0.0001), 1.3 (1.0-1.8) in ♀ (P = 0.13)
      Kuo et al
      • Kuo C.F.
      • Luo S.F.
      • See L.C.
      • et al.
      Hyperuricaemia and accelerated reduction in renal function.
      Retrospective study of hospital-based cohort (63,785)3Hyperuricemia >7.7 mg/dL [♂] or >6.6 mg/dL [♀])Annual eGFR decrease ≥3Age, sex, baseline eGFR,
      By MDRD Study equation.
      azotemia, hypercholesterolemia, hyperglycemia
      Hyperuricemia associated with accelerated eGFR decrease: HR, 1.28 (1.23-1.33); P < 0.001
      Hovind et al
      • Hovind P.
      • Rossing P.
      • Tarnow L.
      • Johnson R.J.
      • Parving H.H.
      Serum uric acid as a predictor for development of diabetic nephropathy in type 1 diabetes—an inception cohort study.
      T1DM (263)18.1Serum uric acid level (per-1 mg/dL increase)Incident micro- or macroalbuminuriaAge, sex, BMI, HbA1c, albuminuria, SCr, total cholesterol, mean BPSerum uric acid independently associated with subsequent development of persistent macroalbuminuria: aHR, 2.93 (1.25-6.86) per 100-μmol/L increase in uric acid (P = 0.013)
      Jalal et al
      • Jalal D.I.
      • Rivard C.J.
      • Johnson R.J.
      • et al.
      Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: findings from the Coronary Artery Calcification in Type 1 Diabetes Study.
      Coronary Artery Calcification in T1DM Study (324)6Serum uric acid level (per 1-mg/dL increase)Composite outcome: incident micro- or macroalbuminuriaAge, sex, duration of DM, BMI, waist circumference, SBP, smoking, HbA1c, albuminuria, SCr, SCysC, HDL-C, triglycerides, use of RAAS blockersSerum uric acid associated with micro-/macroalbuminuria: aOR, 1.8 (1.2-2.8) per 1-mg/dL increase in uric acid (P = 0.005)
      Ficociello et al
      • Ficociello L.H.
      • Rosolowsky E.T.
      • Niewczas M.A.
      • et al.
      High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up.
      Second Joslin Kidney Study; T1DM (355)6Serum uric acid categories (<3.0, 3.0-3.9, 4.0-4.9, 5.0-5.9, ≥6 mg/dL)Early eGFR loss, defined as eGFRcys decrease >3.3%/yAge, sex, HbA1c, eGFRcys, albuminuriaRisk of early eGFR loss increased linearly: 9%, 13%, 20%, 29%, and 36% for uric acid categories in increasing order
      Zoppini et al
      • Zoppini G.
      • Targher G.
      • Chonchol M.
      • et al.
      Serum uric acid levels and incident chronic kidney disease in patients with type 2 diabetes and preserved kidney function.
      Verona DM Study; T2DM (1,449)5Hyperuricemia (≥7.0 mg/dL [♂] or ≥6.5 mg/dL [♀]) or allopurinol useIncident CKD (eGFR <60 or overt proteinuria)Age, sex, BMI, smoking status, DM duration, SBP, HTN treatment, insulin therapy, HbA1c, eGFR, albuminuriaHyperuricemia independently associated with increased risk of incident CKD: aOR, 2.10 (1.16-3.76); P < 0.01
      Altemtam et al
      • Altemtam N.
      • Russell J.
      • El Nahas M.
      A study of the natural history of diabetic kidney disease (DKD).
      Retrospective cohort study of elderly patients with T2DM & CKD3-4 (270)8Serum uric acid (per each 1-mg increase)Progression of CKD (eGFR decrease >2/y)Age, race, SBP, eGFR, HbA1c, proteinuria, vascular comorbiditiesSerum uric acid independently associated with faster kidney disease progression: aOR, 1.16 (1.09-1.39), P = 0.016
      Iseki et al
      • Iseki K.
      • Ikemiya Y.
      • Inoue T.
      • Iseki C.
      • Kinjo K.
      • Takishita S.
      Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort.
      Okinawa General Health Maintenance Association (48,177)7Hyperuricemia (≥7 mg/dL [♂] or ≥6 mg/dL [♀])ESRDAge, SBP, DBP, BMI, proteinuria, Hct, total cholesterol, triglycerides, fasting blood glucose, SCrHyperuricemia an independent risk factor for ESRD in ♀ (aHR, 5.77 [2.3-14.4]; P < 0.001) but not ♂ (aHR, 2.0 [0.90-4.44]; P = NS)
      Yen et al
      • Yen C.J.
      • Chiang C.K.
      • Ho L.C.
      • et al.
      Hyperuricemia associated with rapid renal function decline in elderly Taiwanese subjects.
      Community-based cohort of elderly Taiwanese (519)2.7Serum uric acid level (per 1-mg/dL increase)eGFR <60 or kidney disease progression (decrease in eGFR ≥3/y)Age, sex, BMI, proteinuria, smoking, SCr, Hb, WBC count, HTN and DM statusSerum uric acid independently associated with increased risk of decrease in eGFR (aOR, 1.21 [1.05-1.39]) but not with incident CKD (OR, 0.99 [0.85-1.17])
      Sturm et al
      • Sturm G.
      • Kollerits B.
      • Neyer U.
      • Ritz E.
      • Kronenberg F.
      Uric acid as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study.
      The Mild to Moderate Kidney Disease Study (227)
      Number that completed the study = 177.
      7Serum uric acid level (per 1-mg/dL) increaseProgression of CKD (doubling of baseline SCr or ESRD)Age, sex, proteinuria, GFR, allopurinol useSerum uric acid not associated with increased risk of CKD progression: aHR, 0.95 (0.80-1.13) in all, 1.03 (0.85-1.26) if exclude those taking allopurinol
      Chonchol et al
      • Chonchol M.
      • Shlipak M.G.
      • Katz R.
      • et al.
      Relationship of uric acid with progression of kidney disease.
      CHS (5,808)5Quintiles of uric acidIncident CKD (eGFR <60) or kidney disease progression (decrease in eGFR ≥3/y)Age, sex, race, SCr, BMI, waist circumference, BP, HTN medication use, diuretic use, allopurinol use, glucose, HDL-C, triglycerides, ankle-arm index, carotid IMT, major ECG abnormalities, Hb, CRP, sAlbIndependent association of serum uric acid with progression of kidney disease (aORs of 1.0, 0.88, 1.23, 1.47, and 1.49 for uric acid quintiles 1-5, respectively) but no significant association with incident CKD (aOR, 1.0 [0.89-1.14])
      Madero et al
      • Madero M.
      • Sarnak M.J.
      • Wang X.
      • et al.
      Uric acid and long-term outcomes in CKD.
      MDRD Study (840)10Serum uric acid level (per 1-mg/dL increase)ESRD and deathAge, sex, history of CVD, DM, BMI, HDL-C, SBP, eGFR, sAlb, diuretic use, proteinuria, allopurinol useIn CKD3-4, hyperuricemia not an independent risk factor for ESRD (HR, 1.02 [0.97-1.07]); serum uric acid significantly associated with all-cause and CV mortality
      Ishani et al
      • Ishani A.
      • Grandits G.A.
      • Grimm R.H.
      • et al.
      Association of single measurements of dipstick proteinuria, estimated glomerular filtration rate, and hematocrit with 25-year incidence of end-stage renal disease in the Multiple Risk Factor Intervention Trial.
      MRFIT (12,866)
      All men.
      25Serum uric acid level (per 1-mg/dL increase)Initiation of treatment for ESRD
      Ascertained with USRDS registry data.
      Age, race, family history of DM, smoking, BMI, SBP, fasting glucose, triglycerides, HDL-C, LDL-C, eGFR, Hct, proteinuriaSerum uric acid independently associated with increased risk of ESRD: aHR, 1.16 (1.04-1.29); P = 0.0006
      Hsu et al
      • Hsu C.Y.
      • Iribarren C.
      • McCulloch C.E.
      • Darbinian J.
      • Go A.S.
      Risk factors for end-stage renal disease: 25-year follow-up.
      A large integrated health care delivery system (177,570)24.5Uric acid quartilesESRDAge, sex, race, educational level, BMI, HTN status, DM status, history of kidney disease, history of nocturia, LVH, smoking, alcohol intake, occupational exposure to solvents/fumes/chemicals, SCr, Hb, proteinuriaHigher serum uric acid an independent risk factor for ESRD: HR, 2.14 (1.65-2.77) for highest vs lowest quartile
      Bellomo et al
      • Bellomo G.
      • Venanzi S.
      • Verdura C.
      • Saronio P.
      • Esposito A.
      • Timio M.
      Association of uric acid with change in kidney function in healthy normotensive individuals.
      Healthy normotensive adult blood donors (900)5Serum uric acid level (per 1-mg/dL increase)eGFR loss (>10)Age, sex, BMI, mean BP, fasting glucose, total cholesterol, triglycerides, UACR, smokingSerum uric acid an independent risk factor for decreased kidney function: aHR, 1.23 (1.09-1.39); P = 0.001
      Ben-Dov & Kark
      • Ben-Dov I.Z.
      • Kark J.D.
      Serum uric acid is a GFR-independent long-term predictor of acute and chronic renal insufficiency: the Jerusalem Lipid Research Clinic cohort study.
      The Jerusalem Lipid Research Clinic cohort study (2,449)25Hyperuricemia (upper quintile >6.5 mg/dL [♂] or >5.3 mg/dL [♀])ESRD and AKI defined by hospital discharge recordsNoneHyperuricemia conferred increased risk of ESRD: aHR, 1.94 (1.20-3.14) in ♂, 5.20 (1.90-14.2) in ♀; also significantly associated with increased risk of AKI and all-cause mortality
      Syrjanen et al
      • Syrjanen J.
      • Mustonen J.
      • Pasternack A.
      Hypertriglyceridaemia and hyperuricaemia are risk factors for progression of IgA nephropathy.
      IgA nephropathy (223)10Hyperuricemia (≥7.0 mg/dL [♂] or ≥6.5 mg/dL [♀])Progression of CKD (elevation of SCr above normal and/or SCr ≥20% of baseline)Age, sex, BMI, proteinuria, HTN status, DM status, dyslipidemiaHyperuricemia independently associated with CKD progression only in those with initially normal kidney function: aHR, 4.60 (1.1-19.4)
      Ohno et al
      • Ohno I.
      • Hosoya T.
      • Gomi H.
      • Ichida K.
      • Okabe H.
      • Hikita M.
      Serum uric acid and renal prognosis in patients with IgA nephropathy.
      IgA nephropathy (56)8Hyperuricemia (≥7.0 mg/dL)Progression of CKD (change in CCr)HTN and kidney pathologyHyperuricemia associated with increased risk of kidney disease progression (unadjusted change in CCr: −22.3%±20.8% vs +2.6%±39.4%; P = 0.0238); uric acid associated with decrease in CCr in adjusted analysis (P = 0.046)
      Note: eGFR values given in mL/min/1.73 m2; SCr, in mg/dL. Values in parentheses for HRs and ORs are 95% confidence intervals.
      Abbreviations: aHR, adjusted hazard ratio; AKI, acute kidney injury; aOR, adjusted odds ratio; ARIC, Atherosclerosis Risk in Communities; BMI, body mass index; BP, blood pressure; CCr, creatinine clearance; CHS, Cardiovascular Health Study; CKD, chronic kidney disease; CRP, C-reactive protein; CV, cardiovascular; CVD, cardiovascular disease; DBP, diastolic blood pressure; DM, diabetes mellitus; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; eGFRcys, estimated glomerular filtration rate based on serum cystatin C level; ESRD, end-stage renal disease; F/U, follow-up; GFR, glomerular filtration rate; GGT, γ-glutamyl-transpeptidase; Hb, hemoglobin; HbA1c, hemoglobin A1c; Hct, hematocrit; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; HTN, hypertension; IMT, intima-media thickness; LDL-C, low-density lipoprotein cholesterol; LVH, left ventricular hypertrophy; MDRD, Modification of Diet in Renal Disease; MRFIT, Multiple Risk Factor Intervention Trial; NS, nonsignificant; OR, odds ratio; RAAS, renin-angiotensin-aldosterone system; sAlb, serum albumin; SBP, systolic blood pressure; SCr, serum creatinine; SCysC, serum cystatin C; SUN, serum urea nitrogen; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; UACR, urine albumin-creatinine ratio; USRDS, US Renal Data System; WBC, white blood cell.
      a Allopurinol, lipid-lowering drug, Chinese herbal medicine.
      b By MDRD Study equation.
      c Number that completed the study = 177.
      d All men.
      e Ascertained with USRDS registry data.
      Several epidemiologic studies have examined whether higher serum uric acid levels predict an increased risk of CKD progression. Hsu et al
      • Hsu C.Y.
      • Iribarren C.
      • McCulloch C.E.
      • Darbinian J.
      • Go A.S.
      Risk factors for end-stage renal disease: 25-year follow-up.
      evaluated this in a cohort of 177,570 participants and found that increased serum uric acid level was associated with increased risk of end-stage renal disease over a 25-year follow-up period independently of age, race, sex, body mass index, educational level, blood pressure, diabetes status, serum creatinine level, hemoglobin level, and proteinuria. This association between increased serum uric acid level and CKD progression has been supported further by some other studies,
      • Chonchol M.
      • Shlipak M.G.
      • Katz R.
      • et al.
      Relationship of uric acid with progression of kidney disease.
      • Iseki K.
      • Ikemiya Y.
      • Inoue T.
      • Iseki C.
      • Kinjo K.
      • Takishita S.
      Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort.
      but not all.
      • Sturm G.
      • Kollerits B.
      • Neyer U.
      • Ritz E.
      • Kronenberg F.
      Uric acid as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study.
      • Madero M.
      • Sarnak M.J.
      • Wang X.
      • et al.
      Uric acid and long-term outcomes in CKD.
      For example, an analysis of 840 individuals with stages 3-4 CKD participating in the Modification of Diet in Renal Disease (MDRD) Study did not find uric acid level to be an independent risk factor for progression to chronic kidney failure despite a 10-year follow-up.
      • Madero M.
      • Sarnak M.J.
      • Wang X.
      • et al.
      Uric acid and long-term outcomes in CKD.
      A potential explanation for these conflicted results may be that uric acid clearance is impaired in CKD,
      • Johnson R.J.
      • Kang D.H.
      • Feig D.
      • et al.
      Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease?.
      and as such, serum uric acid level is increased even early on in kidney disease.
      • Rosolowsky E.T.
      • Ficociello L.H.
      • Maselli N.J.
      • et al.
      High-normal serum uric acid is associated with impaired glomerular filtration rate in nonproteinuric patients with type 1 diabetes.
      The MDRD Study adjusted for measured GFR, and perhaps that adjustment may account for its negative findings. In other words, it is possible that uric acid is a sensitive indicator of compromised kidney function and adjustment for accurate measurement of GFR would offset a potential association.
      Another issue that commonly is raised when reviewing results of prospective observational studies of uric acid is that xanthine oxidase, the enzyme that produces uric acid, also produces reactive oxidative species. As such, serum uric acid might simply be a marker of oxidative stress rather than a mediator of disease per se. Unfortunately, such observational studies are naturally incapable of addressing these concerns. To the skeptics, the significant association between uric acid levels and CKD may be explained by such confounders; in other words, renal clearance of uric acid and the xanthine oxidase system. However, the believers may contend that if high uric acid level decreases kidney function early in the disease process, thus increasing the risk of CKD progression, adjusting for baseline GFR would be expected to attenuate any relation between serum uric acid level and chronic kidney failure and that does not exclude a contributing role for hyperuricemia in CKD.

      Uric Acid and Xanthine Oxidase

      As indicated, a major challenge in understanding the potential role of uric acid in CKD is that it is a product of xanthine oxidase in conjunction with reactive oxidative species. Xanthine oxidoreductase exists in 2 forms, xanthine dehydrogenase and xanthine oxidase. When grouped together, the dehydrogenase and oxidase forms catalyze the final step in purine metabolism by converting hypoxanthine to xanthine and xanthine to urate/uric acid. Xanthine oxidoreductase has an important role in survival and development because xanthine oxidoreductase knockout mice die within the first month of their birth secondary to severe renal dysplasia.
      • Ohtsubo T.
      • Rovira I.I.
      • Starost M.F.
      • Liu C.
      • Finkel T.
      Xanthine oxidoreductase is an endogenous regulator of cyclooxygenase-2.
      This seems counterintuitive, but these findings can be explained by impaired COX-2 expression
      • Ohtsubo T.
      • Rovira I.I.
      • Starost M.F.
      • Liu C.
      • Finkel T.
      Xanthine oxidoreductase is an endogenous regulator of cyclooxygenase-2.
      and the accumulation of triglyceride-rich substances, xanthine, and hypoxanthine in renal tubules, which lead to interstitial fibrosis during early development.
      • Ohtsubo T.
      • Matsumura K.
      • Sakagami K.
      • et al.
      Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules.
      Xanthine, albeit rarely, can crystallize in supersaturated urine, leading to stone formation.
      • Pais Jr, V.M.
      • Lowe G.
      • Lallas C.D.
      • Preminger G.M.
      • Assimos D.G.
      Xanthine urolithiasis.
      In contrast, in older rats, an increase in xanthine oxidase activity may contribute to tubulointerstitial injury in experimental hyperlipidemia.
      • Gwinner W.
      • Scheuer H.
      • Haller H.
      • Brandes R.P.
      • Groene H.J.
      Pivotal role of xanthine oxidase in the initiation of tubulointerstitial renal injury in rats with hyperlipidemia.
      Although these detrimental effects of xanthine oxidase may be merely due to increased oxidative stress, preliminary evidence suggests that uric acid is a mediator of xanthine oxidase effects. For example, the renal dysplasia phenotype found in xanthine oxidoreductase knockout animals is identical to that seen in COX-2 deficiency. Considering that uric acid ingestion has been shown to stimulate COX-2 expression both in vivo and in vitro,
      • Ohtsubo T.
      • Rovira I.I.
      • Starost M.F.
      • Liu C.
      • Finkel T.
      Xanthine oxidoreductase is an endogenous regulator of cyclooxygenase-2.
      it is logical to conclude that uric acid may be at least a partial mediator of xanthine oxidoreductase effects. Unfortunately, little is known about xanthine oxidoreductase activity in models of kidney disease; we identified only one study in our review in which xanthine oxidase activity was reportedly decreased in the 5/6 nephrectomy model.
      • Vaziri N.D.
      • Freel R.W.
      • Hatch M.
      Effect of chronic experimental renal insufficiency on urate metabolism.
      Although findings of this experimental model suggest that the increase in uric acid level seen in CKD may be related to reduced renal clearance as opposed to increased xanthine oxidoreductase activity, virtually no study has examined xanthine oxidoreductase activity in human CKD.

      Treatment of Hyperuricemia in CKD

      In general, xanthine oxidase inhibitors such as allopurinol or febuxostat are the preferred agents to decrease uric acid levels due to their effectiveness in both overproducers and undersecretors of uric acid. Allopurinol is metabolized by xanthine oxidase to oxypurinol, and both substrates act to inhibit xanthine oxidase.
      • Gaffo A.L.
      • Saag K.G.
      Management of hyperuricemia and gout in CKD.
      Patients with CKD may be at increased risk of toxicity with allopurinol (eg, rash, gastrointestinal intolerance, leukopenia, and severe hypersensitivity reaction) because oxypurinol is cleared by the kidney.
      • Hande K.R.
      • Noone R.M.
      • Stone W.J.
      Severe allopurinol toxicity Description and guidelines for prevention in patients with renal insufficiency.
      In addition, some investigators have suggested that insufficient dosing of allopurinol in patients with CKD and gout leads to undertreatment.
      • Dalbeth N.
      • Stamp L.
      Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events.
      Thus, it is widely recommended to start with low dosages of allopurinol in patients with CKD and slowly titrate it to an effective dose. Febuxostat, a nonpurine selective xanthine oxidase inhibitor, has been shown to be safe and effective for decreasing serum uric acid levels
      • Becker M.A.
      • Schumacher H.R.
      • Espinoza L.R.
      • et al.
      The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial.
      and represents a pharmacologic alternative to allopurinol in hyperuricemic patients who are unable to tolerate allopurinol. Other agents that can be used to decrease uric acid levels include uricosuric agents such as probenecid and benzbromarone (the latter is unavailable in the United States), in addition to losartan and fenofibrates (both drugs exert mild uricosuric effects).
      Use of a uricosuric agent such as probenecid is generally lauded as a better approach than xanthine oxidase inhibition to evaluate the potential role of uric acid in disease states, given that such treatment would eliminate the confounding effect of xanthine oxidase inhibition. However, this may differ in CKD. Uricosuric agents obviously would increase urinary uric acid excretion, and this increase in uric acid on the luminal side of the nephron may be associated with the same deleterious effects. In addition, increased urinary uric acid excretion may increase the risk of crystallization, thus leading to further inflammation and higher risk of kidney stones.
      In any event, the potential benefit of decreasing uric acid level on CKD progression has been evaluated in only a handful of studies (shown in Table 2). In a small randomized trial by Siu et al,
      • Siu Y.P.
      • Leung K.T.
      • Tong M.K.
      • Kwan T.H.
      Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.
      54 hyperuricemic patients with mild to moderate CKD were assigned to allopurinol (100-300 mg/d with the goal of normalizing serum uric acid levels) versus no therapy (control) and followed up for 12 months. At the end of follow-up, a significantly larger number of participants in the control group (16% vs 46%; P = 0.015) achieved the combined end point of a serum creatinine level increase ≥40%, dialysis, or death. More recently, a larger study conducted by Goicoechea et al
      • Goicoechea M.
      • de Vinuesa S.G.
      • Verdalles U.
      • et al.
      Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.
      included 113 hyperuricemic patients with CKD randomly assigned to either allopurinol (100 mg/d) or a control group (no therapy). At the end of the 2-year follow-up, estimated GFR decreased by 3.3±1.2 mL/min/1.73 m2 in the control group; in the allopurinol group, estimated GFR increased by 1.3±1.3 mL/min/1.73 m2 (P = 0.018). The major limitations of both these interventional studies are the relatively small number of patients and the absence of a placebo arm. One recent open-label randomized controlled trial conducted by Shi et al
      • Shi Y.
      • Chen W.
      • Jalal D.
      • et al.
      Clinical outcome of hyperuricemia in IgA nephropathy: a retrospective cohort study and randomized controlled trial.
      evaluated allopurinol treatment in 40 patients with immunoglobulin A nephropathy. After 6 months of treatment, allopurinol did not significantly alter kidney disease progression or proteinuria, although it significantly improved blood pressure in these patients. In addition to the open-label design and small number of participants, the short duration of follow-up is a major limitation of this study. The only double-blinded randomized placebo controlled trial that examined the effect of decreasing uric acid levels on diabetic nephropathy
      • Momeni A.
      • Shahidi S.
      • Seirafian S.
      • Taheri S.
      • Kheiri S.
      Effect of allopurinol in decreasing proteinuria in type 2 diabetic patients.
      included 40 patients with type 2 diabetes followed up for 4 months and evaluated proteinuria as an outcome. The small number of participants, short duration of follow-up, and lack of assessment of kidney function are notable limitations of this study, although it showed a significant decrease in proteinuria with allopurinol treatment, which appeared to be complementary to renin-angiotensin-aldosterone system blockade.
      Table 2Main Interventional Studies to Decrease Serum Uric Acid Levels in CKD
      StudyStudy Design and PopulationTreatmentStudy End PointsMain Findings
      Siu et al
      • Siu Y.P.
      • Leung K.T.
      • Tong M.K.
      • Kwan T.H.
      Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.
      RCT of 54 hyperuricemic patients with mild to moderate CKD12 mo of either allopurinol, 100-300 mg/d, or no treatmentDecreased kidney function with SCr ≥40% of baseline, initiation of dialysis, or deathNonsignificant trend toward lower SCr in the treatment group (P = 0.08); overall, 16% (4/25) of allopurinol group reached the combined end points vs 46.1% (12/26) in control group (P = 0.015)
      Goicoechea et al
      • Goicoechea M.
      • de Vinuesa S.G.
      • Verdalles U.
      • et al.
      Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.
      RCT of 113 hyperuricemic patients with mild to moderate CKD24 mo of either allopurinol, 100 mg/d, or no treatmentProgression of CKD (defined as eGFR decrease >0.2/mo), CV events, hospitalizations for any cause, or deathΔeGFRs of −3.3 ± 1.2 (control) and +1.3 ± 1.3 (allopurinol group), P = 0.018; compared with controls, allopurinol treatment slowed CKD progression in a Cox regression model (adjusted for age, sex, diabetes, uric acid) and reduced risk of CV events and number of hospitalizations (aHR, 0.29; 95% CI, 0.09-0.86; P = 0.026)
      Kanbay et al
      • Kanbay M.
      • Ozkara A.
      • Selcoki Y.
      • et al.
      Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearence, and proteinuria in patients with normal renal functions.
      Case-control study of 59 hyperuricemic patients with eGFR >60 and 21 normouricemic controls; only hyperuricemic patients received allopurinol
      In other words, not a placebo-controlled RCT.
      3 mo of allopurinol, 300 mg/deGFR <60eGFR significantly increased (from 79.2 ± 32 to 92.9 ± 37; P = 0.008) and BP and plasma CRP decreased in allopurinol group; no significant change in control group
      Talaat & el-Sheikh
      • Talaat K.M.
      • el-Sheikh A.R.
      The effect of mild hyperuricemia on urinary transforming growth factor beta and the progression of chronic kidney disease.
      Intervention trial of allopurinol withdrawal in 50 hyperuricemic patients with CKD3-4 treated with allopurinol12 mo after allopurinol withdrawalChanges in eGFR and urinary TGFβ1Significant acceleration of rate of eGFR loss and significant increases in BP and urinary TGFβ1 only in those who were not receiving ACEi
      Miao et al
      • Miao Y.
      • Ottenbros S.A.
      • Laverman G.D.
      • et al.
      Effect of a reduction in uric acid on renal outcomes during losartan treatment: a post hoc analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan trial.
      Placebo-controlled RCT of patients treated with losartan in a post hoc analysis of the RENAAL trial; N=1,342 patients with type 2 diabetes and nephropathyPost hoc analysis of first 6 mo of treatmentProgression of CKD (defined as doubling of SCr or ESRD)Losartan decreased serum uric acid by 0.16 (95% CI, 0.30-0.01) mg/dL (P = 0.031) vs placebo; risk of renal events was decreased by 6% (95% CI, 10%-3%) per 0.5-mg/dL decrement in serum uric acid during the first 6 mo of treatment after adjustment for age, sex, treatment assignment (losartan or placebo), eGFR, SBP, albuminuria, serum albumin, ACEi or ARB use at baseline, changes in albuminuria and eGFR
      Note: eGFR given in mL/min/1.73 m2.
      Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; aHR, adjusted hazard ratio; ARB, angiotensin receptor blocker; BP, blood pressure; CI, confidence interval; CKD, chronic kidney disease; CRP, C-reactive protein; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HR, hazard ratio; OR, odds ratio; SBP, systolic blood pressure; SCr, serum creatinine; RCT, randomized clinical trial; RENAAL, Reduction of Endpoints in Non–Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan; TGF, transforming growth factor.
      a In other words, not a placebo-controlled RCT.
      The potential nephroprotective effect of decreasing uric acid levels in addition to traditional therapies for CKD is supported further by the findings of a post hoc analysis of the RENAAL (Reduction of Endpoints in Non–Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan) trial.
      • Miao Y.
      • Ottenbros S.A.
      • Laverman G.D.
      • et al.
      Effect of a reduction in uric acid on renal outcomes during losartan treatment: a post hoc analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan trial.
      In this study, the risk of renal events was decreased by 6% for every 0.5-mg/dL decrement in serum uric acid level during the first 6 months of treatment with losartan. The lower uric acid levels in the losartan group most likely are due to the uricosuric effect of this drug. Although such studies suggest that decreasing uric acid levels may slow CKD progression, considering their many limitations, a role for uric acid–lowering therapies in CKD cannot be advocated based on their results. Rather, results of such studies imply that properly designed randomized placebo-controlled studies need to be conducted to assess objectively whether uric acid–lowering therapies would benefit patients with CKD.
      In addition to the mentioned trials, some recent studies suggest that treating hyperuricemia may prevent or delay the onset of CKD. A randomized double-blinded study by Feig et al
      • Feig D.I.
      • Soletsky B.
      • Johnson R.J.
      Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial.
      showed that treating hyperuricemia in adolescents with newly diagnosed hypertension was effective at lowering blood pressure. Similar to the studies mentioned, allopurinol was used to decrease serum uric acid levels and resulted in significant improvements in systolic and diastolic blood pressure compared with placebo. It is uncertain whether this is an effective antihypertensive approach as opposed to the current standard of care, but the results of this small clinical trial raise the possibility that decreasing uric acid levels early may prevent the onset of kidney disease. In an attempt to evaluate whether decreasing uric acid levels would prevent kidney disease onset, Kanbay et al
      • Kanbay M.
      • Huddam B.
      • Azak A.
      • et al.
      A randomized study of allopurinol on endothelial function and estimated glomular filtration rate in asymptomatic hyperuricemic subjects with normal renal function.
      conducted a small case-controlled study. Here, 59 hyperuricemic individuals with estimated GFR ≥60 mL/min/1.73 m2 were treated with 300 mg of allopurinol daily for a 3-month period and were noted to have improvements in systolic and diastolic blood pressure, as well as a significant increase in estimated GFR (proteinuria was unchanged in this trial). However, results of such a study need to be confirmed in larger placebo-controlled trials. Whether pharmacological lowering of uric acid levels is more effective than dietary and lifestyle modifications prior to CKD onset also will need to be assessed.

      Hyperuricemia in Kidney Transplantation

      Hyperuricemia is common in patients after kidney transplantation.
      • Baroletti S.
      • Bencivenga G.A.
      • Gabardi S.
      Treating gout in kidney transplant recipients.
      Although increased uric acid levels in this setting may represent decreased transplant function, hyperuricemia has been reported even in patients with intact transplant function.
      • Kim K.M.
      • Kim S.S.
      • Han D.J.
      • Yang W.S.
      • Park J.S.
      • Park S.K.
      Hyperuricemia in kidney transplant recipients with intact graft function.
      Several factors contribute to hyperuricemia after transplantation, such as cyclosporine therapy, use of diuretics, and the high prevalence of metabolic syndrome and diabetes in kidney transplant recipients.
      • Mazali F.C.
      • Mazzali M.
      Uric acid and transplantation.
      Although hyperuricemia contributes to cyclosporine-associated nephrotoxicity in animal models,
      • Mazali F.C.
      • Johnson R.J.
      • Mazzali M.
      Use of uric acid-lowering agents limits experimental cyclosporine nephropathy.
      we are unaware of studies that have evaluated the role of uric acid–lowering therapies in kidney transplant patients, and observational studies evaluating uric acid as a predictor of transplant dysfunction have shown conflicted results.
      • Armstrong K.A.
      • Johnson D.W.
      • Campbell S.B.
      • Isbel N.M.
      • Hawley C.M.
      Does uric acid have a pathogenetic role in graft dysfunction and hypertension in renal transplant recipients?.
      • Akalin E.
      • Ganeshan S.V.
      • Winston J.
      • Muntner P.
      Hyperuricemia is associated with the development of the composite outcomes of new cardiovascular events and chronic allograft nephropathy.
      • Meier-Kriesche H.U.
      • Schold J.D.
      • Vanrenterghem Y.
      • Halloran P.F.
      • Ekberg H.
      Uric acid levels have no significant effect on renal function in adult renal transplant recipients: evidence from the Symphony Study.
      • Akgul A.
      • Bilgic A.
      • Ibis A.
      • Ozdemir F.N.
      • Arat Z.
      • Haberal M.
      Is uric acid a predictive factor for graft dysfunction in renal transplant recipients?.
      • Haririan A.
      • Nogueira J.M.
      • Zandi-Nejad K.
      • et al.
      The independent association between serum uric acid and graft outcomes after kidney transplantation.
      • Kim K.M.
      • Kim S.S.
      • Yun S.
      • et al.
      Uric acid contributes to glomerular filtration rate deterioration in renal transplantation.
      • Kim K.M.
      • Kim S.S.
      • Han D.J.
      • Yang W.S.
      • Park J.S.
      • Park S.K.
      Hyperuricemia in kidney transplant recipients with intact graft function.
      • Boratynska M.
      • Karbowska A.
      • Klinger M.
      The effect of hyperuricemia on endothelial biomarkers and renal function in kidney allograft recipients.
      These studies are summarized in Table 3.
      Table 3Observational Studies Evaluating Uric Acid as a Predictor of Reduced Graft Function in Patients With a Kidney Transplant
      StudyNF/U (y)Independent VariableStudy OutcomeAdjustments ConsideredFindings
      Armstrong et al
      • Armstrong K.A.
      • Johnson D.W.
      • Campbell S.B.
      • Isbel N.M.
      • Hawley C.M.
      Does uric acid have a pathogenetic role in graft dysfunction and hypertension in renal transplant recipients?.
      907Hyperuricemia (>7 mg/dL for men, and >6 mg/dL for women) at least 6 mo posttransplantationeGFR, and change in eGFR
      eGFR calculated using the MDRD Study equation.
      Age, sex, race, weight, BMI, time since transplantation, history of CVD, dyslipidemia, DM, smoking status, baseline eGFR and proteinuria, calcium, phosphate, albumin, Hb, homocysteine, CRP, medicationsHyperuricemia independently predictive of eGFR (β estimate, −22.2; 95% CI, −41 to −3.2; P = 0.02); hyperuricemia not associated with change in eGFR
      Akalin et al
      • Akalin E.
      • Ganeshan S.V.
      • Winston J.
      • Muntner P.
      Hyperuricemia is associated with the development of the composite outcomes of new cardiovascular events and chronic allograft nephropathy.
      3074.3Hyperuricemia 6 mo posttransplantation (≥7 mg/dL for men and ≥6.5 mg/dL for women)Composite of death, transplant loss, new CV event, or biopsy-proven CANAge, race, sex, eGFR <50, cyclosporine use, cadaveric kidneyHyperuricemia associated with more events (P < 0.001 for K-M curve); in group with eGFR <50, hyperuricemia associated with 45% event rate vs 21% in normouricemia(P = 0.038)
      Meier-Kriesche et al
      • Meier-Kriesche H.U.
      • Schold J.D.
      • Vanrenterghem Y.
      • Halloran P.F.
      • Ekberg H.
      Uric acid levels have no significant effect on renal function in adult renal transplant recipients: evidence from the Symphony Study.
      8523Serum uric acid levels 1 mo posttransplantation (per 1 mg/dL) and uric acid tertileseGFR
      eGFR calculated using creatinine clearance.
      Donor type, immunosuppressive treatment arm, ethnicity, baseline eGFRUric acid and eGFR were collinear; uric acid associated with reduced eGFR at 3 y (P = 0.005), but this became not significant after adjusting for baseline eGFR
      Akgul et al
      • Akgul A.
      • Bilgic A.
      • Ibis A.
      • Ozdemir F.N.
      • Arat Z.
      • Haberal M.
      Is uric acid a predictive factor for graft dysfunction in renal transplant recipients?.
      1333Hyperuricemia 1 mo posttransplantation (>7 mg/dL for men and >6 mg/dL for women)CAN (biopsy proven)Age, donor source, no. of HLA mismatches, duration of dialysis, HTN, acute rejection, serum cholesterolUric acid not associated with CAN (P > 0.05)
      Haririan et al
      • Haririan A.
      • Nogueira J.M.
      • Zandi-Nejad K.
      • et al.
      The independent association between serum uric acid and graft outcomes after kidney transplantation.
      2126Serum uric acid level within the first 6 mo posttransplantation (per 1 mg/dL) and hyperuricemia (>7 mg/dL for men and >6.5 mg/dL for women)Transplant and patient survival, transplant functionAge, sex, race, retransplantation, BMI, HLA mismatch, early transplant function, SCr, DM, induction agent, acute rejectionUric acid associated with transplant loss (HR, 1.26 [95% CI, 1.03-1.53] per 1-mg/dL increase; P = 0.026) and hyperuricemia independently predicted transplant loss (HR, 1.92 [95% CI, 1.1-3.4]; P = 0.029)
      Kim et al
      • Kim K.M.
      • Kim S.S.
      • Yun S.
      • et al.
      Uric acid contributes to glomerular filtration rate deterioration in renal transplantation.
      5564Hyperuricemia (>7 mg/dL for men and >6 mg/dL for women)Transplant dysfunction with >50% loss of kidney function (eGFR
      eGFR calculated using the MDRD Study equation.
      )
      Age, sex, weight, donor type, time since transplantation, HTN, DM, immunosuppressive regimen, serum calcium, serum phosphorusHyperuricemia associated with transplant dysfunction: unadjusted HR, 1.31 (P < 0.001); aHR, 1.45 (P < 0.001)
      Kim et al
      • Kim K.M.
      • Kim S.S.
      • Han D.J.
      • Yang W.S.
      • Park J.S.
      • Park S.K.
      Hyperuricemia in kidney transplant recipients with intact graft function.
      3565Mean uric acid levels obtained every 3 mo (starting 6 mo posttransplantation) modelled as a continuous variable (per 1 mg/dL) and categorical hyperuricemia (>7 mg/dL for men and >6 mg/dL for women)eGFR
      eGFR calculated using the MDRD Study equation.
      Age, sex, weight, donor type, time since transplantation, HTN, DM, immunosuppressive regimen, serum calcium, serum phosphorusUric acid did not predict eGFR
      Boratynska et al
      • Boratynska M.
      • Karbowska A.
      • Klinger M.
      The effect of hyperuricemia on endothelial biomarkers and renal function in kidney allograft recipients.
      982.5Hyperuricemia (>7 mg/dL for men and >6 mg/dL for women)eGFRNoneeGFR significantly higher in normo- vs hyperuricemic patients at baseline, but SCr and eGFR were similar in both groups at study end
      Note: eGFR values given in mL/min/1.73 m2.
      Abbreviations: aHR, adjusted hazard ratio; BMI, body mass index; CAN, chronic allograft nephropathy; CI, confidence interval; CRP, C-reactive protein; CV, cardiovascular; CVD, cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; F/U, follow-up; Hb, hemoglobin; HR, hazard ratio; HTN, hypertension; K-M, Kaplan-Meier; MDRD, Modification of Diet in Renal Disease; SCr, serum creatinine.
      a eGFR calculated using the MDRD Study equation.
      b eGFR calculated using creatinine clearance.

      Conclusions

      Hyperuricemia is common in CKD. Experimental evidence suggests that uric acid itself may harm patients with CKD by contributing to increased inflammation and CKD progression. Although controversial, these observations are supported by many large prospective observational studies that show increased serum uric acid levels that predict the development and progression of CKD in various populations. Interventional studies, although sparse, suggest that decreasing uric acid levels in hyperuricemic patients with CKD is safe and might slow CKD progression. The currently published studies are promising and suggest that there may be a role for uric acid–lowering therapy in patients with CKD. However, it is important to note that these studies are limited by the small number of participants and lack of a placebo arm. Considering the significant limitations of the present literature, further studies are needed before we can advocate decreasing uric acid levels in patients with CKD. In addition, the best therapeutic strategy to decrease uric acid levels in this patient population needs to be determined.

      Acknowledgements

      Support: This review was supported by the following grants: 1K23DK088833, 1R01 DK081473-01A1, and 1R01DK078112-01A2, as well as ISN Fellowship.
      Financial Disclosure: The authors declare that they have no relevant financial interests.

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