Uric Acid Metabolism and the Kidney

C H A P T E R

35 Uric Acid Metabolism and the Kidney Duk-Hee Kanga and Richard J. Johnsonb a

Division of Nephrology, Department of Internal Medicine, Ewha Women’s University School of Medicine, Seoul, Korea, b Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

INTRODUCTION Hyperuricemia and gout are common in CKD patients. This relationship has been noted since the 1800s.1 Over the years there has been great controversy over the biologic significance of hyperuricemia, with some individuals arguing it is a major cause of CKD,2 and others viewing the rise in S[UA] as strictly an epiphenomenon.3 During the last 10 to 15 years, interest in uric acid has reawakened with the realization that an elevated S[UA] can predict the development of CKD4,5 and by experimental studies that document a causal role for uric acid in both the development and progression of CKD.6–9 Today there is great interest in the potential that uric acid may represent a remediable risk factor for CKD. We provide an update on uric acid and the kidney, focusing both on uric acid metabolism and a critical evaluation of the current evidence for uric acid as a risk factor for CKD.

URIC ACID METABOLISM Generation of Uric Acid Uric acid is generated from metabolic conversion of either exogenous (dietary) or endogenous purines, primarily in the liver and intestine. The immediate precursor of uric acid is xanthine, which is metabolized to uric acid by either xanthine oxidase or by its isoform, xanthine dehydrogenase. Approximately twothirds of total body urate is produced endogenously, while the remaining one-third is accounted for by dietary purines.10 Purine-rich foods include beer, meat, P. Kimmel & M. Rosenberg (Eds): Chronic Renal Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-411602-3.00035-4

poultry, seafood, mushrooms, spinach, asparagus and cauliflower.11 Uric acid can also be generated by fructose, which is produced both from nucleotide turnover and from increased synthesis from amino acid precursors.12,13 Alcohol can also increase uric acid levels from increased nucleotide turnover and reduced urinary excretion.14,15 In healthy men, the urate pool averages about 1200 mg with a mean turnover rate of 700 mg/day.16 In humans, uric acid represents the final enzymatic degradation product in purine metabolism. In most mammals a liver enzyme, uricase, degrades uric acid to 5-hydroxyisourate and eventually allantoin.17 However, in humans, and great and lesser apes, uricase was mutated approximately 10–15 million years ago, and as such, S[UA] levels are higher in these species compared to other mammals.18,19 Nevertheless, much of uric acid is still metabolized in humans. First, uric acid is an antioxidant and can react with a variety of substances, resulting in the formation of allantoin (from superoxide), triuret (from reaction with peroxynitrite) or 6-aminouracil (from reaction with nitric oxide).20,21 These products account for less than 1% of uric acid metabolism, but can be elevated in patients with CKD and those treated with maintenance dialysis. However, as much as onethird of uric acid enters the gut via transporters (ABCG2 and SLC2A9) where it is metabolized by gut bacteria, and can be excreted in the stool as uric acid or downstream products.22

Excretion of Uric Acid One-third of the total uric acid excreted is via bacterial metabolism in the gut, with two-thirds excreted by the kidneys. Normal urinary urate excretion ranges between

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Causes of Hyperuricemia and Hypouricemia

Basolateral

Apical

Reabsorption OAT4

UA

URAT1

UA

SLC2A9 (Glut9)

UA

OAT10 NPT1

UA

NPT4

OAT1

UA

MRP4 ABCG2

UA

OAT3

Secretion

FIGURE 35.1  Renal urate transport. Renal urate transport is thought to occur primarily, if not exclusively, in the proximal tubule. The two most important transporters involved in reabsorption are URAT1 (on the apical membrane) and SLC2A9 (on the basolateral membrane). Important transporters for urate secretion include ABCG2, MRP4, and others. Source: Adapted from Reference 26.

250 and 750 mg per day.23 Urate, the form of uric acid in the circulation, is freely filtered at the glomerulus, followed by both reabsorption and secretion in the proximal tubule. The fractional urate excretion is 8 to 10% in the healthy adult. Some adaptation occurs in people with impaired renal function, in whom the fractional excretion increases to the range of 10 to 20%.23 During the last decade there have been great advances in our understanding of urate transport by the kidney, largely due to the characterization and isolation of transporters mainly or exclusively restricted to urate transport. Membrane vesicle studies have suggested the existence of two major mechanisms modulating urate reabsorption and secretion, consisting of a voltage-sensitive pathway and a urate–organic anion exchanger.24,25 Recently several of these transporters/ channels have been identified (Figure 35.1). Organic anion transporters 1–10 (OAT1–10) and the urate transporter-1 (URAT-1) belong to the SLC22A gene family, which facilitate the movement of a variety of chemically unrelated endogenous and exogenous organic anions including uric acid.27 URAT-1, which is encoded by SLC22A12, is the major organic anion exchanger for uric acid on the apical (luminal brush border) side of the proximal tubular cell.28 In the human kidney, urate is transported via URAT-1 across the apical membrane of proximal tubular cells, in exchange for anions being transported back into the tubular lumen to maintain electrical balance. URAT-1 has a high affinity for urate together with lactate, ketones, α-ketoglutarate, and related compounds. Pyrazinamide, probenecid, losartan and benzbromarone all inhibit urate uptake in exchange

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for chloride at the luminal side of the cell by competition with the urate exchanger. OAT-4 exhibits 53% amino acid homology with URAT1. After uptake into cells, urate then moves across the basolateral membrane into the blood by other organic anion transporters, of which the most important is SLC2A9 (also known as GLUT9).29,30 SLC2A9 is highly expressed in the kidney, gut and liver. Individuals with mutations in either URAT1 or SLC2A9 have severe hypouricemia with marked uricosuria.31,32 Urate secretion appears to be mediated principally by a voltage-sensitive urate transporter, which is expressed ubiquitously and localizes to the apical side of the proximal tubule.33 One candidate is MRP4, which is a novel human renal apical organic anion efflux transporter. MRP4 is a member of the ATP-binding cassette transporter family. MRP4 mediates secretion of urate and other organic anions such as cAMP, cGMP, and methotrexate across the apical membrane of human renal proximal tubular cells.34 Another important voltage-sensitive transporter for uric acid is ABCG2. ABCG2 is expressed in both the proximal tubule and gut and may have a critical role in the movement of uric acid into the gut.22 Another protein involved in renal transport of urate is Tamm-Horsfall protein (THP), also known as uromodulin. THP is exclusively expressed and secreted by epithelial cells of the thick ascending limb.35 THP has antibacterial effects.35 THP also co-localizes with the Na,K,2Cl transporter in lipid rafts in the apical cell membrane, suggesting a functional interaction.36 Mutations in the human uromodulin gene have been identified in people with type 2 medullary cystic kidney disease and familial juvenile hyperuricemic nephropathy.37,38 THP polymorphisms have also been associated with hyperuricemia,39 which is inconsistent with the conventional wisdom that uric acid handling is restricted to the proximal tubule. However, there is some evidence that some urate secretion in the rat can occur distal to the proximal tubule. Furthermore, the THP mutation may lead to sodium wasting and diuresis,40 possibly resulting in stimulation of urate reabsorption proximally.

CAUSES OF HYPERURICEMIA AND HYPOURICEMIA Hyperuricemia Hyperuricemia is arbitrarily defined as a S[UA] greater than 7.0  mg/dL in men and greater than 6.5 mg/dL in women.41 S[UA] levels in the population appear to be rising throughout the last century, likely as a consequence of changes in diet.42 Uric acid levels tend to be higher in certain populations (such as African

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Americans and Pacific Islanders), with certain phenotypes (such as obesity and metabolic syndrome) and with special diets. Uric acid also has a circadian variation, with the highest levels in the early morning.43 The serum urate concentration is determined by the balance between urate production and elimination. Hyperuricemia may occur from excessive production of urate (overproduction) or decreased elimination (underexcretion). Frequently a combination of both processes occurs in the same patient. Furthermore, uric acid levels may vary in the same individual by as much as 1 to 2 mg/dL during the course of a day, due to the effects of diet, hydration and exercise. Genetic mechanisms mediating hyperuricemia include overproduction due to a lack of hypoxanthine–guanine phosphoribosyltransferase (HGPRT) or overactivation of phosphoribosyl pyrophosphate synthetase (PRPPS). Subjects with Lesch–Nyhan syndrome (due to a mutation of HGPRT on the X chromosome) present with neurologic manifestations (mental retardation, choreoathetosis, and dystonia) in childhood and have an increased risk for nephrolithiasis, renal failure and gout. A partial deficiency of HGPRT may manifest later in life as recurrent gout and/or nephrolithiasis (Kelley–Seegmiller syndrome).44 Other genetic mechanisms include subjects with the uromodulin mutation, who develop hyperuricemia (due to underexcretion) with early and progressive renal disease. Certain populations such as indigenous peoples living in Oceania also have higher uric acid levels than Caucasian populations.45 Finally, African Americans also have higher uric acid levels and a twofold higher incidence of gout compared to Caucasian or Asian populations.46 However, this could reflect diets higher in fructose-containing sugars rather than genetic mechanisms.47 Hyperuricemia may also result from diets high in purines, ethanol or fructose. The effect of alcohol is in part related to increased urate synthesis, which is due to enhanced turnover of ATP during the conversion of acetate to acetyl-CoA as part of the metabolism of ethanol.14 In addition, acute alcohol consumption causes increased lactate production. Because lactate is an antiuricosuric agent, it reduces renal urate excretion and exacerbates hyperuricemia.15 Fructose (a simple sugar present in sucrose, table sugar, high fructose corn syrup, honey, and fruits) can also induce a rapid rise in S[UA], due in part to its rapid phosphorylation in hepatocytes with ATP consumption, intracellular phosphate depletion, and the stimulation of AMP deaminase with the generation of uric acid.48 Chronic fructose consumption also stimulates the synthesis of uric acid from amino acid precursors. The marked increase in fructose intake may have a role in the rising levels of S[UA] and obesity worldwide.49 In addition, uric acid levels may be affected by exercise, with moderate exercise reducing urate

levels (probably by increasing renal blood flow) and severe exercise causing a rise in S[UA] (probably due to ATP consumption with adenosine and xanthine formation). Urate levels vary between genders. Premenopausal women have lower S[UA] than males due to the uricosuric effect of estrogen.50 S[UA] tends to increase in the setting of low blood volume and/or low salt diet due to its increased reabsorption in proximal tubules. Hyperuricemia is particularly common in patients with obesity and/or metabolic syndrome (thought to be secondary to the effect of insulin to stimulate uric acid reabsorption) and in those with untreated hypertension (in association with reduced renal blood flow). Thiazides also increase uric acid reabsorption in the proximal tubule by decreasing blood volume and via a direct interaction with the organic anion exchanger. Other drugs, such as cyclosporine, pyrazinamide, and low-dose aspirin increase S[UA], primarily by interfering with renal urate excretion. In addition, the generation of organic anions by lactate or β-hydroxybutyrate may interfere with urate secretion in the proximal tubule and cause a rise in S[UA] levels. Chronic lead ingestion can also cause hyperuricemia by reducing urate excretion. In contrast, acute toxicity with extremely high lead concentrations may cause hypouricemia, due to proximal tubular injury and the induction of a Fanconi syndrome.51,52 Uric acid is also increased in the setting of tissue hypoxia or with cell turnover. With tissue hypoxia, ATP is consumed and the isoform, xanthine oxidase, is induced, resulting in increased local uric acid concentrations. Circulating uric acid levels are thus high in subjects with congestive heart failure, acute and chronic high altitude hypoxia, congenital cyanotic heart disease, and with obstructive sleep apnea.53,54 Uric acid levels are commonly elevated with certain malignancies, especially leukemia and lymphoma, and levels may sharply rise following chemotherapy. Finally, uric acid has a tendency to be elevated in subjects with polycythemia vera and other myeloproliferative disorders. In the setting of reduced renal function, the fractional excretion of urate increases, but not enough to fully compensate for the reduction in GFR. As a consequence S[UA] levels rise in CKD patients. Uric acid excretion by the gastrointestinal tract is also enhanced,55 and therefore S[UA] levels tend to be only mildly elevated in patients with CKD, and gout is relatively rare. However, by the time dialysis is initiated, half of CKD patients are hyperuricemic.56,57

Hypouricemia Low uric acid levels (levels less than 2.0 mg/dL) can occur via a variety of mechanisms, including with

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liver disease (due to decreased production), Fanconi syndrome (due to impaired reabsorption by the proximal tubule) and with diabetic glucosuria (which causes uricosuria). Drugs such as probenecid, highdose salicylates, sulfinpyrazone, benziodarone, benz­ bromarone and losartan are uricosuric. Allopurinol, febuxostat, and oxypurinol lower S[UA] by blocking xanthine oxidase. Some statins also lower uric acid.58 Recombinant uricase (rasburicase) can markedly reduce S[UA] and is approved for use in patients with tumor lysis syndrome. There is also a hereditary hypouricemia syndrome, particularly common in Japan, due to a mutation in the URAT-1 gene.59 A similar hypouricemia syndrome has also been observed with mutations in SLC2A9.31 Subjects carrying these mutations are particularly prone to develop AKI following vigorous exercise.32

URIC ACID AND RENAL DISEASE Hyperuricemia as a Primary Cause of CKD Hyperuricemia is common in CKD patients. Although in some cases the hyperuricemia is due to specific disease entities, uric acid excretion is impaired in patients with a reduced GFR. Therefore, in many cases the rise in S[UA] may be simply secondary to CKD, although this does not rule out the possibility that uric acid may still have a role in modifying progression of renal disease.60 Gout was considered a cause of CKD, dating back to the mid-19th century. Natural history studies prior to the availability of uric acid-lowering drugs reported that as many as 25% of gouty subjects developed proteinuria, 50% developed renal insufficiency, and 10 to 25% developed ESRD.2 Renal histologic changes in patients with gout include arteriolosclerosis, glomerulosclerosis, and tubulointerstitial fibrosis, often with focal deposition of monosodium urate in interstitial areas, especially the outer medulla.61 This led to the supposition that the disease “gouty nephropathy” might be due to urate crystal deposition in the kidney. However, studies in the late 1970s challenged this hypothesis, as the intrarenal crystal deposition was focal and could not explain the diffuse disease that was commonly observed. In addition, the renal lesions observed in gout were similar to the findings one observes in patients with hypertensive renal disease (nephrosclerosis) or with aging, suggesting these latter conditions might be responsible for the diffuse renal scarring.3 Studies using uric acid-lowering therapy to improve renal function in gouty subjects also showed variable results, leading to skepticism regarding whether the disease truly exists.3,62

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New Insights Regarding the Entity of Primary Hyperuricemic Nephropathy Renewed interest in the role of gout and/or asymptomatic hyperuricemia in the pathogenesis of CKD began when it was realized that it was inappropriate to ascribe hypertension to explain every case of renal insufficiency in the gouty patient, since most subjects with essential hypertension have relatively preserved renal function.63 Another implicit assumption was that gouty nephropathy had to be due to crystal deposition, and the possibility that uric acid might mediate effects through crystal-independent mechanisms was not considered.63 Furthermore, the analysis also assumed that the presence of hypertension was a separate cause of renal disease and that it had to be independent of the uric acid.64 This led to a proposal to reinvestigate the role of uric acid in CKD. Subsequently numerous epidemiological studies have shown that S[UA] is an independent risk factor for developing CKD (Table 35.1).60 In one Japanese study, hyperuricemia conferred a 10.8-fold increased risk in women and a 3.8-fold increased risk in men for the development of CKD, compared to those with normal uric acid levels.5 This higher relative risk in subjects with hyperuricemia was independent of age, body mass index, systolic blood pressure, total cholesterol, serum albumin, glucose, history of smoking, alcohol use, exercise habits, hematuria, and even proteinuria. An elevated uric acid was also independently associated with a markedly increased risk of ESRD in another study of more than 49,000 male railroad workers.65 A second insight came from experimental studies in which chronic mild hyperuricemia was induced in rats, which developed hypertension and progressive renal disease without intra-renal crystal deposition.6,8 The primary mechanism appeared to be due to the ability of increased S[UA] levels to induce glomerular hypertension and renal vasoconstriction.66 Early in the course the rats developed arteriolar thickening and rarely hyalinosis of the preglomerular arterioles, often accompanied by glomerular hypertrophy.7 Proteinuria appeared subsequently with the development of worsening vascular disease, glomerulosclerosis, and interstitial fibrosis. The lesion was identical to that observed with nephrosclerosis of hypertension, with aging-associated glomerulosclerosis, and with gouty nephropathy, except for the absence of crystal deposition that had been observed in the latter condition.6–9 This finding suggests that chronic hyperuricemia may cause renal disease and hypertension via a crystalindependent pathway (Figure 35.2). Further studies showed that uric acid was able to induce endothelial dysfunction in vitro.67 Several mechanisms appear to be operative, including the ability of

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35.  Uric Acid Metabolism and the Kidney

TABLE 35.1  Elevated S[UA] Predicts Development of CKD Location

Population

Follow-up

Type

Independent

Author, Year

Japan

6403 adults

2 yrs

CKD

Yes

Iseki, 2001

Japan

48,177 adults

10 yrs

ESRD

Women

Iseki, 2004

Thailand

3499 adults

12 yrs

CKD

Yes

Domrongkitchaiporn, 2005

USA

5808 adults

5 yrs

CKD

No

Chonchol, 2007

Austria

21,457 adults

7 yrs

CKD

Yes

Obermayr, 2008

USA

13,338 adults

8.5 yrs

CKD

Yes

Weiner, 2008

Austria

17,375 adults

7 yrs

CKD

Yes

Obermayr, 2008

USA

177,500 adults

25 yrs

ESRD

Yes

Hsu, 2009

USA

355 type 1 diabetes*

6 yrs

CKD

Yes

Ficociello, 2010

Italy

900 adults

5 yrs

CKD

Yes

Bellomo, 2010

Japan

7078 adults

5 yrs

CKD

Yes

Sonoda, 2011

Taiwan

94,422 adults

3.5 yrs

CKD

Men

Wang, 2011

Israel

2449 adults

26 yrs

ESRD

Yes

Ben-Dov, 2011

Japan

14,399 adults

5 yrs

CKD

Yes

Yamada, 2011

USA

488 renal transplants

1 yr

Graft loss

Yes

Haririan, 2011

China

1410 adults

4 yrs

CKD

Yes

Zhang, 2012

Korea

14,939 adults

10.2 yrs

CKD

Men

Mok, 2012

Italy

1449 type 2 diabetics

5 yrs

CKD

Yes

Zoppini, 2012

*Subjects with albuminuria Source: From Johnson RJ, Nakagawa T, Jalal D, Sanchez-Lozada LG, Kang DH, Ritz E. Uric acid and chronic kidney disease: which is chasing which? Nephrol Dial Transplant. 2013; 28(9):2221–2228. Reproduced with permission.

Uric acid Entering into cells via uric acid transporters Renal tubular cell

Endothelial cell

Smooth muscle cell

Juxtaglomerular cell

NAPDH Oxidase activation mitochondrial ROS

EMT Inflammation

↓Proliferation ↓Nitric oxide Inflammation

↑Proliferation ↑COX-2 expression Inflammation

↑Renin

Hypertension

Interstitial fibrosis

Arteriopathy with microvascular rarefaction

Primary kidney disease and/or aggravation of preexisting kidney disease

FIGURE 35.2  Proposed mechanism for uric acid-induced renal disease. Uric acid can have direct effects on cells and may also induce hemodynamic changes in the kidney. Some of the effects include the stimulation of oxidative stress in the cell, including stimulation of NADPH oxidase and oxidative stress in mitochondria. The oxidative stress is associated with tubular changes (epithelial mesenchymal transition, EMT). Endothelial cells show impaired nitric oxide bioavailability and reduced proliferation. Vascular smooth muscle cells produce growth factors, thromboxane and inflammatory mediators. Renin is also stimulated. Glomerular hypertension and reduced renal blood flow result, and over time vascular changes (arteriolosclerosis), glomerulosclerosis and tubulointerstitial fibrosis develop. ROS: reactive oxygen species, COX: cyclooxygenase.

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uric acid to block uptake of the substrate (L-arginine) for nitric oxide, increased degradation of intracellular L-arginine, and a scavenging of nitric oxide by uric acid or uric acid-induced oxidants.67–70 Indeed, uric acid inhibits endothelial release of nitric oxide, blocks endothelial cell proliferation and induces senescence via activation of the local renin-angiotensin system and induction of oxidative stress.67,71,72 Uric acid also stimulates vascular smooth muscle cell proliferation in vitro via uptake of urate into the cell with activation of MAP kinases, nuclear transcription factors (including NF-κB and AP-1), and inflammatory mediators (including monocyte chemoattractant protein-1 and C-reactive protein).9,73–75 Uric acid also inhibits tubular cell proliferation and induces epithelial-to-mesenchymal phenotype transition of renal tubular cells with the production of extracellular matrix.76 Hyperuricemic rats displayed evidence of endothelial dysfunction (with low serum nitrites reflecting low NO) and increased intrarenal renin expression.8,67 The in vivo renal changes could be reversed by lowering uric acid with uric acid-lowering drugs such as allopurinol and febuxostat.6,9,77–79 In addition, micropuncture studies performed on the hyperuricemic rats demonstrated glomerular hypertension with a reduction in renal plasma flow.77 All these mechanisms can lead to renal injury. One of the key mechanisms by which uric acid appears to work is by inducing intracellular oxidative stress and inflammation72,80–83 (Figure 35.2). This is paradoxical, in that uric acid is an antioxidant that can bind and inactivate superoxide and peroxynitrite, and some studies suggest that uric acid may represent one of the more important antioxidants in the circulatory system.84,85 However, the binding of uric acid with peroxynitrite generates radicals (aminocarbonyl radical and triuretcarbonyl radical) as the peroxynitrite is inactivated, and urate–peroxynitrite reaction also generates alkylating species.20,86 In addition, when uric acid enters cells it stimulates NADPH oxidase, leading to both intracellular and mitochondrial oxidative stress. Indeed, uric acid induces oxidative stress in a large variety of cell types, including vascular endothelial and smooth muscle cells, renal tubular epithelial cells, hepatocytes, islet cells, and adipocytes.72,80–83 Taken together, uric acid may induce primary kidney disease or accelerate the progression of CKD by effects on the renal microvasculature, renal tubules and interstitium.

Clinical Manifestations of Hyperuricemic Nephropathy Most patients with longstanding gout have asymptomatic renal involvement with either normal or only mild renal insufficiency.2,87 The majority have

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hypertension.88 Renal blood flow is usually disproportionately low for the degree of decrement in renal function.89 Fractional excretion of uric acid is usually less than 10%. Proteinuria occurs in the minority of cases, and, when present, is usually in the non-nephrotic range. The urinary sediment is also usually benign. However, hypertension is frequent, occurring in 50 to 60% of subjects, and increasing in prevalence as renal function worsens. Renal biopsy shows chronic changes indistinguishable from chronic hypertensive nephropathy, with chronic glomerulosclerosis, tubulointerstitial fibrosis and renal microvascular disease.2 Intrarenal crystals may occasionally be observed, but their presence or absence does not rule out a role for uric acid in the pathogenesis of the kidney disease.63 Nonetheless, a disproportionately elevated S[UA] in relation to impaired renal function (such as uric acid level greater than 9 mg/dL for a S[Cr] of less than 1.5 mg/dL, uric acid greater than 10 mg/dL for a S[Cr] of 1.5 to 2.0 mg/dL, and uric acid of greater than 12 mg/dL when S[Cr] is greater than 2.0 mg/dL) would suggest there is a primary process raising S[UA] besides reduction in GFR.

Role of Hyperuricemia in Progression of CKD While there is extensive epidemiological evidence that an elevated S[UA] is an independent risk factor for the development of CKD (Table 35.1), it remains controversial whether an elevated S[UA] is a risk factor for progression of kidney disease in subjects with pre-existing CKD. This is because patients with CKD may have elevated S[UA] levels simply due to the reduction in urate excretion that accompanies reduced GFR. For example, neither the Modification of Diet in Renal Disease Study nor the Mild to Moderate Kidney Disease Study could show uric acid to be an independent risk factor for progression in subjects with pre-existing CKD.90,91 One recent study in middle-aged and old Taiwanese subjects found an elevated uric acid level increased the risk of renal disease, after adjustment for other metabolic risk factors such as gender, BMI, cholesterol, triglyceride, blood pressure and blood sugar. An interesting finding from this study was that S[UA] was independently associated with eGFR only in stage 3 CKD, but not in stage 4 or 5 CKD subjects. There may be a variety of reasons why an elevated S[UA] may not predict CKD in subjects with established CKD. One potential explanation is that factors associated with reduced GFR itself may have major effects on driving renal progression that dwarf the biological mechanisms by which uric acid may cause renal disease. Thus, impaired renal function is known to result in hypertension from impaired salt excretion, to cause endothelial dysfunction, and to be associated with inflammation.92 Many people with severe CKD also

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35.  Uric Acid Metabolism and the Kidney

suffer from malnutrition, and these patients may have low uric acid levels due to a reduction in food intake (since uric acid levels are driven in part by diet). It is also possible that in the setting of a pro-oxidant state such as CKD, the antioxidant benefits of uric acid may outweigh its pro-inflammatory and pro-oxidant effects. More studies need to be performed to better understand the complexity of uric acid and its role in established CKD.

Role of Uric Acid-Lowering Therapy in CKD There have been a limited number of studies to examine the effect of uric acid-lowering in the development or progression of CKD. Kanbay et  al. reported that treatment of healthy subjects with asymptomatic hyperuricemia improved renal function.93 Siu et al. also reported that the treatment of asymptomatic hyperuricemia delayed disease progression, with a lesser increase in blood pressure following a 12-month treatment of allopurinol in patients with stage 3 CKD.94 Shi et  al. evaluated the effects of allopurinol in subjects with IgA nephropathy and mild CKD, but since the control group did not progress, it was not possible to judge whether allopurinol was protective or not.95 In another prospective study of 113 patients with stable CKD with eGFR less than 60 mL/min/1.73m2, Goicoechea et al.96 demonstrated that 100 mg/day allopurinol significantly slowed the progression of renal disease after 23.4 ± 7.8 months of treatment compared to controls, although the relative benefit was mild (difference in GFR of 4.6 mL/min/1.73 m2). However, no differences in blood pressure or in albuminuria were observed in the allopurinol group compared to the control group. Currently there is an ongoing NIH-funded study to evaluate whether lowering uric acid is of benefit in participants with diabetes and early CKD. While early studies suggest some potential benefit of lowering uric acid on renal function, one of the more striking benefits appears to be on heart disease. In the study by Goicoechea et al., there was a significant reduction in cardiovascular events in subjects with CKD. Terawaki et  al.97 also noted a nearly 50% reduction in cardiovascular events by allopurinol in people with CKD due to hypertension. Furthermore, Kao et al. noted that allopurinol could improve left ventricular mass and endothelial dysfunction in CKD patients.98 These studies suggest that lowering uric acid may be of benefit to reduce cardiovascular events in CKD.

Uric Acid and ESRD In subjects with normal renal function, an elevated S[UA] is almost always associated with increased cardiovascular risk, and a smaller rise in cardiovascular

risk occurs in subjects with low S[UA] levels (“J curve” of mortality). However, in ESRD patients, the high risk for mortality is generally in those subjects with the lowest S[UA] (reverse J curve).56,57 The reason for this finding is unknown, but it is important to note that the lower quartile for S[UA] in the ESRD population is still quite high compared to normal subjects. One potential explanation for the association of lower uric acid levels with increased mortality may relate to the fact that subjects in the lowest uric acid category are often those with the poorest nutrition, such as subjects who are bed-ridden or suffering from stroke.57 It is also possible that S[UA] might act similarly to obesity or hypertension as a risk factor associated with improved survival in ESRD patients. Further studies are necessary to better understand this complex relationship.

Hyperuricemia, Hypertension, and Metabolic Syndrome Hyperuricemia is commonly associated with other conditions, including obesity, metabolic syndrome, fatty liver, and hypertension. For decades the increase in S[UA] in these conditions has been thought to be secondary, and due to effects of hyperinsulinemia or obesity to alter uric acid excretion or metabolism. However, more recent studies have raised the exciting possibility that uric acid may have a causal role in these conditions.99 For example, experimentally-induced hyperuricemia has been shown to result in hypertension.6 In various models of metabolic syndrome and fatty liver, lowering uric acid with allopurinol has been reported to be protective.100,101 Epidemiological studies demonstrate that an elevated S[UA] is a consistent independent risk factor for hypertension, metabolic syndrome, diabetes, fatty liver and obesity.99,102 Pilot clinical interventional studies also report some benefit of lowering S[UA] on blood pressure, insulin resistance, and systemic inflammation.103–105 Clearly more studies need to be performed, but there is increasing evidence that uric acid may be a true risk factor not only for CKD, but also for metabolic syndrome, hypertension and fatty liver.

Challenges to the Uric Acid Hypothesis The uric acid hypothesis is not without controversy. For example, some continue to argue that uric acid is actually a pure antioxidant, and that the benefits of lowering S[UA] with allopurinol are due to the ability of xanthine oxidase inhibitors to also block oxidants generated during the production of uric acid from xanthine. In support of this hypothesis, it has been repeatedly observed that allopurinol therapy improves endothelial dysfunction in humans, yet treatment with a uricosuric agent was reported to have no effect.106 However,

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REFERENCES

the mechanism by which uric acid causes CVD appears to be due to the intracellular effects of uric acid, so treatments that block uric acid synthesis (such as allopurinol) would likely be more effective than uricosuric agents. Furthermore, in some cell culture studies the benefit of allopurinol can be prevented if uric acid is added to the media,107 suggesting it is the uric acid which is responsible for the effect. In addition, in a recent clinical trial, both allopurinol and probenecid (a uricosuric drug) lowered blood pressure significantly in obese prehypertensive adolescents.104 The other major challenge is that genome wide association studies (GWAS) have found several polymorphisms in urate transport that predict hyperuricemia and gout, but they do not appear to predict hypertension or diabetes.108 This has been interpreted as meaning that it is unlikely that S[UA] is a true risk factor for these conditions. However, the polymorphisms alter the transport of uric acid in and out of cells, so it is unclear how these polymorphisms affect intracellular uric acid levels where the uric acid is working. We need more studies on this complex topic before any conclusions can be made firmly.

Should People with CKD and Hyperuricemia be Treated? Hyperuricemia is common in CKD patients, but it remains unclear if lowering uric acid is beneficial. Certainly the experimental, epidemiological, and pilot clinical studies raise the possibility that lowering S[UA] may benefit both renal function and the cardiovascular risk in these patients, but we need larger, randomized trials before such therapy should be routinely embraced. We must also remember that allopurinol can induce a Stevens–Johnson syndrome, and rarely AKI. While the serious reactions from allopurinol may be minimized by testing the HLA status of patients and excluding treatment in those who are HLA-B58 positive,109 we still need to be careful to do no harm. As such, we recommend treatment only for those subjects who have severe hyperuricemia (uric acid greater than 10 mg/dL in men and greater than 9 mg/dL in women), and only after discussing the pros and cons of such therapy with the patient.

CONCLUSIONS S[UA] levels are determined by the balance of uric acid generation and excretion via the kidney. Decreased GFR and altered expression/function of uric acid transporters in renal tubules can lead to elevations of S[UA]. Hyperuricemia is epidemiologically associated with increased risk for AKI, and experimental studies

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suggest uric acid may have a contributory role. There is also accumulating evidence supporting hyperuricemia as a true risk factor for CKD, based on recent epidemiologic, clinical and experimental observations. Nonetheless, there are still controversies regarding the causative role of uric acid in kidney disease. As such, we recommend a large randomized clinical trial be conducted to determine if uric acid-lowering therapy provides benefit in hyperuricemic subjects with CKD before routine lowering of uric acid levels is recommended.

References 1. Johnson G. On the diseases of the kidney. London: John W Parker and Son; 1852. 2. Talbott JH, Terplan KL. The kidney in gout. Medicine (Baltimore) 1960;39:405–67. 3. Beck LH. Requiem for gouty nephropathy. Kidney Int 1986;30:280–7. 4. 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. Am J Kidney Dis 2004;44:642–50. 5. 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. Hypertens Res 2001;24:691–7. 6. Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001;38:1101–6. 7. Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, et  al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 2002;282:F991–7. 8. Nakagawa T, Mazzali M, Kang DH, Kanellis J, Watanabe S, Sanchez-Lozada LG, et al. Hyperuricemia causes glomerular hypertrophy in the rat. Am J Nephrol 2003;23:2–7. 9. Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol 2002;13:2888–97. 10. Schumacher Jr. HR. The pathogenesis of gout. Cleve Clin J Med 2008;75(Suppl. 5):S2–S4. 11. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purinerich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med 2004;350:1093–103. 12. Raivio KO, Becker A, Meyer LJ, Greene ML, Nuki G, Seegmiller JE. Stimulation of human purine synthesis de novo by fructose infusion. Metabolism 1975;24:861–9. 13. Emmerson BT. Effect of oral fructose on urate production. Ann Rheum Dis 1974;33:276–80. 14. Faller J, Fox IH. Ethanol-induced hyperuricemia: evidence for increased urate production by activation of adenine nucleotide turnover. N Engl J Med 1982;307:1598–602. 15. Lieber CS, Jones DP, Losowsky MS, Davidson CS. Interrelation of uric acid and ethanol metabolism in man. J Clin Invest 1962;41:1863–70. 16. Scott JT, Holloway VP, Glass HI, Arnot RN. Studies of uric acid pool size and turnover rate. Ann Rheum Dis 1969;28:366–73. 17. Kahn K, Serfozo P, Tipton PA. Identification of the true product of the urate oxidase reaction. J Am Chem Soc 1997;119:5435–42. 18. Oda M, Satta Y, Takenaka O, Takahata N. Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol Biol Evol 2002;19:640–53.

VI.  FLUID/ELECTROLYTE DISORDERS IN CHRONIC KIDNEY DISEASE

426

35.  Uric Acid Metabolism and the Kidney

19. Keebaugh AC, Thomas JW. The evolutionary fate of the genes encoding the purine catabolic enzymes in hominoids, birds, and reptiles. Mol Biol Evol 2010;27:1359–69. 20. Gersch C, Palii SP, Imaram W, Kim KM, Karumanchi SA, Angerhofer A, et al. Reactions of peroxynitrite with uric acid: formation of reactive intermediates, alkylated products and triuret, and in vivo production of triuret under conditions of oxidative stress. Nucleos Nucleot Nucleic Acids 2009;28:118–49. 21. Gersch C, Palii SP, Kim KM, Angerhofer A, Johnson RJ, Henderson GN. Inactivation of nitric oxide by uric acid. Nucleos Nucleot Nucleic Acids 2008;27:967–78. 22. Ichida K, Matsuo H, Takada T, Nakayama A, Murakami K, Shimizu T, et  al. Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat Commun 2012;3:764. 23. Maesaka JK, Fishbane S. Regulation of renal urate excretion: a critical review. Am J Kidney Dis 1998;32:917–33. 24. Roch-Ramel F, Guisan B, Diezi J. Effects of uricosuric and anti­ uricosuric agents on urate transport in human brush-border membrane vesicles. J Pharmacol Exp Ther 1997;280:839–45. 25. Roch-Ramel F, Werner D, Guisan B. Urate transport in brushborder membrane of human kidney. Am J Physiol 1994;266: F797–805. 26. Anzai N, Jutabha P, Amonpatumrat-Takahashi S, Sakurai H. Recent advances in renal urate transport: characterization of candidate transporters indicated by genome-wide association studies. Clin Exp Nephrol 2012;16:89–95. 27. Hediger MA, Johnson RJ, Miyazaki H, Endou H. Molecular physiology of urate transport. Physiology (Bethesda) 2005;20:125–33. 28. Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, et  al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002;417:447–52. 29. Anzai N, Ichida K, Jutabha P, Kimura T, Babu T, Jin CJ, et  al. Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem 2008;283:26834–8. 30. Bibert S, Hess SK, Firsov D, Thorens B, Geering K, Horisberger JD, et  al. Mouse GLUT9: evidences for a urate uniporter. Am J Physiol Renal Physiol 2009;297:F612–9. 31. Dinour D, Gray NK, Campbell S, Shu X, Sawyer L, Richardson W, et al. Homozygous SLC2A9 mutations cause severe renal hypouricemia. J Am Soc Nephrol 2010;21:64–72. 32. Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, Endou H, et  al. Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol 2004;15:164–73. 33. Lipkowitz MS, Leal-Pinto E, Rappoport JZ, Najfeld V, Abramson RG. Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter. J Clin Invest 2001;107:1103–15. 34. Van Aubel RA, Smeets PH, van den Heuvel JJ, Russel FG. Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites. Am J Physiol Renal Physiol 2005;288:F327–33. 35. Scolari F, Caridi G, Rampoldi L, Tardanico R, Izzi C, Pirulli D, et  al. Uromodulin storage diseases: clinical aspects and mechanisms. Am J Kidney Dis 2004;44:987–99. 36. Bachmann S, Mutig K, Bates J, Welker P, Geist B, Gross V, et  al. Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice. Am J Physiol Renal Physiol 2005;288:F559–67. 37. Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, et  al. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 2002;39:882–92. 38. Turner JJ, Stacey JM, Harding B, Kotanko P, Lhotta K, Puig JG, et  al. Uromodulin mutations cause familial

39.

40.

41. 42. 43.

44.

45. 46.

47.

48.

49.

50. 51. 52.

53.

54.

55. 56.

57.

58.

juvenile hyperuricemic nephropathy. J Clin Endocrinol Metab 2003;88:1398–401. Han J, Liu Y, Rao F, Nievergelt CM, O’Connor DT, Wang X, et al. Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels. Kidney Int 2013;83:733–40. Gersch MS, Sautin YY, Gersch CM, Henderson G, Bankir L, Johnson RJ. Does Tamm-Horsfall protein-uric acid binding play a significant role in urate homeostasis? Nephrol Dial Transplant 2006;21:2938–42. Terkeltaub RA. Clinical practice. Gout. N Engl J Med 2003;349:1647–55. Johnson RJ, Titte S, Cade JR, Rideout BA, Oliver WJ. Uric acid, evolution and primitive cultures. Semin Nephrol 2005;25:3–8. Kanabrocki EL, Third JL, Ryan MD, Nemchausky BA, Shirazi P, Scheving LE, et al. Circadian relationship of serum uric acid and nitric oxide. JAMA 2000;283:2240–1. Augoustides-Savvopoulou P, Papachristou F, Fairbanks LD, Dimitrakopoulos K, Marinaki AM, Simmonds HA. Partial hypoxanthine-guanine phosphoribosyltransferase deficiency as the unsuspected cause of renal disease spanning three generations: a cautionary tale. Pediatrics 2002;109:E17. Merriman TR, Dalbeth N. The genetic basis of hyperuricaemia and gout. Joint Bone Spine 2011;78:35–40. Alderman MH, Cohen H, Madhavan S, Kivlighn S. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension 1999;34:144–50. Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, et  al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr 2007;86:899–906. Van den Berghe G. Fructose: metabolism and short-term effects on carbohydrate and purine metabolic pathways. Prog Biochem Pharmacol 1986;21:1–32. Johnson RJ, Perez-Pozo SE, Sautin YY, Manitius J, SanchezLozada LG, Feig DI, et  al. Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes? Endocr Rev 2009;30:96–116. Nicholls A, Snaith ML, Scott JT. Effect of oestrogen therapy on plasma and urinary levels of uric acid. Br Med J 1973;1:449–51. Wilson VK, Thomson ML, Dent CE. Amino-aciduria in lead poisoning; a case in childhood. Lancet 1953;265:66–8. Inglis JA, Henderson DA, Emmerson BT. The pathology and pathogenesis of chronic lead nephropathy occurring in Queensland. J Pathol 1978;124:65–76. Jefferson JA, Escudero E, Hurtado ME, Kelly JP, Swenson ER, Wener MH, et  al. Hyperuricemia, hypertension, and proteinuria associated with high-altitude polycythemia. Am J Kidney Dis 2002;39:1135–42. Hare JM, Johnson RJ. Uric acid predicts clinical outcomes in heart failure: insights regarding the role of xanthine oxidase and uric acid in disease pathophysiology. Circulation 2003;107:1951–3. Sorensen LB. Role of the intestinal tract in the elimination of uric acid. Arthritis Rheum 1965;8:694–706. Suliman ME, Johnson RJ, Garcia-Lopez E, Qureshi AR, Molinaei H, Carrero JJ, et al. J-shaped mortality relationship for uric acid in CKD. Am J Kidney Dis 2006;48:761–71. Lee SM, Lee AL, Winters TJ, Tam E, Jaleel M, Stenvinkel P, et al. Low serum uric acid level is a risk factor for death in incident hemodialysis patients. Am J Nephrol 2009;29:79–85. Athyros VG, Elisaf M, Papageorgiou AA, Symeonidis AN, Pehlivanidis AN, Bouloukos VI, et  al. Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Am J Kidney Dis 2004;43:589–99.

VI.  FLUID/ELECTROLYTE DISORDERS IN CHRONIC KIDNEY DISEASE

427

REFERENCES

59. Iwai N, Mino Y, Hosoyamada M, Tago N, Kokubo Y, Endou H. A high prevalence of renal hypouricemia caused by inactive SLC22A12 in Japanese. Kidney Int 2004;66:935–44. 60. Johnson RJ, Nakagawa T, Jalal D, Sanchez-Lozada LG, Kang DH, Ritz E. Uric acid and chronic kidney disease: which is chasing which? Nephrol Dial Transplant 2013;28:2221–8. 61. Bluestone R, Waisman J, Klinenberg JR. The gouty kidney. Semin Arthritis Rheum 1977;7:97–113. 62. Nickeleit V, Mihatsch MJ. Uric acid nephropathy and end-stage renal disease – review of a non-disease. Nephrol Dial Transplant 1997;12:1832–8. 63. Johnson RJ, Kivlighn SD, Kim YG, Suga S, Fogo AB. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis 1999;33:225–34. 64. Johnson RJ, Tuttle KR. Much ado about nothing, or much to do about something? The continuing controversy over the role of uric acid in cardiovascular disease. Hypertension 2000;35:E10. 65. Tomita M, Mizuno S, Yamanaka H, Hosoda Y, Sakuma K, Matuoka Y, et  al. Does hyperuricemia affect mortality? A prospective cohort study of Japanese male workers. J Epidemiol 2000;10:403–9. 66. Sanchez-Lozada LG, Tapia E, Rodriguez-Iturbe B, Johnson RJ, Herrera-Acosta J. Hemodynamics of hyperuricemia. Semin Nephrol 2005;25:19–24. 67. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int 2005;67:1739–42. 68. Park JH, Jin YM, Hwang S, Cho DH, Kang DH, Jo I. Uric acid attenuates nitric oxide production by decreasing the interaction between endothelial nitric oxide synthase and calmodulin in human umbilical vein endothelial cells: a mechanism for uric acid-induced cardiovascular disease development. Nitric Oxide 2013;32C:36–42. 69. Zharikov S, Krotova K, Hu H, Baylis C, Johnson RJ, Block ER, et  al. Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells. Am J Physiol Cell Physiol 2008;295:C1183–90. 70. Schwartz IF, Grupper A, Chernichovski T, Hillel O, Engel A, Schwartz D. Hyperuricemia attenuates aortic nitric oxide generation, through inhibition of arginine transport in rats. J Vasc Res 2011;48:252–60. 71. Kang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol 2005;16:3553–62. 72. Yu MA, Sanchez-Lozada LG, Johnson RJ, Kang DH. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acidinduced endothelial dysfunction. J Hypertens 2010;28:1234–42. 73. Kang DH, Han L, Ouyang X, Kahn AM, Kanellis J, Li P, et  al. Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter. Am J Nephrol 2005;25:425–33. 74. Watanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J, Lan H, et  al. Uric acid, hominoid evolution, and the pathogenesis of saltsensitivity. Hypertension 2002;40:355–60. 75. Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, et al. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 2003;41:1287–93. 76. Ryu ES, Kim MJ, Shin HS, Jang YH, Choi HS, Jo I, et al. Uric acidinduced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease. Am J Physiol Renal Physiol 2013;304:F471–80. 77. Sanchez-Lozada LG, Tapia E, Santamaria J, Avila-Casado C, Soto V, Nepomuceno T, et  al. Mild hyperuricemia induces

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88. 89.

90.

91.

92.

93.

94.

vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats. Kidney Int 2005;67:237–47. Sanchez-Lozada LG, Tapia E, Soto V, Avila-Casado C, Franco M, Wessale JL, et al. Effect of febuxostat on the progression of renal disease in 5/6 nephrectomy rats with and without hyperuricemia. Nephron Physiol 2008;108:p69–78. Sanchez-Lozada LG, Tapia E, Soto V, Avila-Casado C, Franco M, Zhao L, et  al. Treatment with the xanthine oxidase inhibitor febuxostat lowers uric acid and alleviates systemic and glomerular hypertension in experimental hyperuricaemia. Nephrol Dial Transplant 2008;23:1179–85. Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol 2007;293:C584–96. Corry DB, Eslami P, Yamamoto K, Nyby MD, Makino H, Tuck ML. Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J Hypertens 2008;26:269–75. Roncal-Jimenez CA, Lanaspa MA, Rivard CJ, Nakagawa T, Sanchez-Lozada LG, Jalal D, et  al. Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake. Metabolism 2011;60:1259–70. Lanaspa MA, Sanchez-Lozada LG, Choi YJ, Cicerchi C, Kanbay M, Roncal-Jimenez CA, et  al. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J Biol Chem 2012;287:40732–44. Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis 2000;148:131–9. Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 1981;78:6858–62. Imaram W, Gersch C, Kim KM, Johnson RJ, Henderson GN, Angerhofer A. Radicals in the reaction between peroxynitrite and uric acid identified by electron spin resonance spectroscopy and liquid chromatography mass spectrometry. Free Radic Biol Med 2010;49:275–81. Yu TF, Berger L. Impaired renal function gout: its association with hypertensive vascular disease and intrinsic renal disease. Am J Med 1982;72:95–100. Wallace SL. Gout and hypertension. Arthritis Rheum 1975;18:721–4. Yu TF, Berger L, Dorph DJ, Smith H. Renal function in gout. V. Factors influencing the renal hemodynamics. Am J Med 1979;67:766–71. Madero M, Sarnak MJ, Wang X, Greene T, Beck GJ, Kusek JW, et al. Uric acid and long-term outcomes in CKD. Am J Kidney Dis 2009;53:796–803. 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. Exp Gerontol 2008;43:347–52. Stenvinkel P, Ketteler M, Johnson RJ, Lindholm B, Pecoits-Filho R, Riella M, et  al. IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia – the good, the bad, and the ugly. Kidney Int 2005;67:1216–33. Kanbay M, Huddam B, Azak A, Solak Y, Kadioglu GK, Kirbas I, et  al. A randomized study of allopurinol on endothelial function and estimated glomerular filtration rate in asymptomatic hyperuricemic subjects with normal renal function. Clin J Am Soc Nephrol 2011;6:1887–94. Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006;47:51–9.

VI.  FLUID/ELECTROLYTE DISORDERS IN CHRONIC KIDNEY DISEASE

428

35.  Uric Acid Metabolism and the Kidney

95. Shi Y, Chen W, Jalal D, Li Z, Chen W, Mao H, et al. Clinical outcome of hyperuricemia in IgA nephropathy: a retrospective cohort study and randomized controlled trial. Kidney Blood Press Res 2012;35:153–60. 96. Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincón A, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 2010;5:1388–93. 97. Terawaki H, Nakayama M, Miyazawa E, Murata Y, Nakayama K, Matsushima M, et  al. Effect of allopurinol on cardiovascular incidence among hypertensive nephropathy patients: the Gonryo study. Clin Exp Nephrol 2013;17(4):549–53. 98. Kao MP, Ang DS, Gandy SJ, Nadir MA, Houston JG, Lang CC, et  al. Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease. J Am Soc Nephrol 2011;22:1382–9. 99. Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M, et  al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 2013;62(10):3307–15. 100. Baldwin W, McRae S, Marek G, Wymer D, Pannu V, Baylis C, et  al. Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes 2011;60:1258–69. 101. Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, et  al. A causal role for uric acid in fructoseinduced metabolic syndrome. Am J Physiol Renal Physiol 2006;290:F625–31.

102. Feig DI, Madero M, Jalal DI, Sanchez-Lozada LG, Johnson RJ. Uric acid and the origins of hypertension. J Pediatr 2013;162:896–902. 103. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA 2008;300:924–32. 104. Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension 2012;60:1148–56. 105. Ogino K, Kato M, Furuse Y, Kinugasa Y, Ishida K, Osaki S, et al. Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Fail 2010;3:73–81. 106. George J, Carr E, Davies J, Belch JJ, Struthers A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 2006;114:2508–16. 107. Lanaspa MA, Sanchez-Lozada LG, Cicerchi C, Li N, RoncalJimenez CA, Ishimoto T, et al. Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver. PLoS One 2012;7:e47948. 108. Yang Q, Kottgen A, Dehghan A, Smith AV, Glazer NL, Chen MH, et al. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ Cardiovasc Genet 2010;3:523–30. 109. Jung JW, Song WJ, Kim YS, Joo KW, Lee KW, Kim SH, et  al. HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency. Nephrol Dial Transplant 2011;26:3567–72.

VI.  FLUID/ELECTROLYTE DISORDERS IN CHRONIC KIDNEY DISEASE