Is It Time to Revise the Normal Range of Serum Uric Acid Levels?

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Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2014; 18: 1295-1306 Is it time to revise the normal range of serum uric acid levels?

G. DESIDERI 1, G. CASTALDO 2,3 , A. LOMBARDI 4, M. MUSSAP 5, A. TESTA 6, R. PONTREMOLI 7, L. PUNZI 8, C. BORGHI 9

1Geriatric Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy 2Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy 3CEINGE-Advanced Biotechnologies, Naples, Italy 4General Practiotioner, Florence, Italy 5Laboratory Medicine Unit, IRCCS AOU San Martino-IST, University-Hospital, Genoa, Italy 6General Practitioner, Castellamonte, Italy 7Department of Internal Medicine, University of Genoa and IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy 8Rheumatology Unit, Department of Medicine DIMED, University of Padova, Padova, Italy 9Internal Medicine Unit, Aging and Kidney Disease Department, University of Bologna, Bologna, Italy

Abstract. – The actual reference range of µmol/L) seems to better identify true “healthy serum uric acid has been assessed according to subjects” and should reasonably be considered its variations among healthy individuals. i.e. for all subjects. those without clinical evidence of gout. By this approach, serum uric acid values between 3.5 Key Words: and 7.2 mg/dL in adult males and post - Uric acid, Hyperuricemia, Gout, Cardiovascular dis - menopausal women and between 2.6 and 6.0 ease, Renal disease. mg/dL in premenopausal women have been identified as normal in many countries. However, this definition of normal range of serum uric acid in the general population is inevitably influ - enced by what we consider as “normal”, since Introduction the absence of gout flares does not necessarily imply the absence of uric acid-related damage. The prevalence of hyperuricaemia and gout Indeed, a growing body of evidence indicates has been growing in Western countries for the that silent deposition of monosodium urate crys - last few decades 1,2 . Gout is currently the most tals as a result of hyperuricaemia may occur and prevalent inflammatory arthritis in developed lead to early destructive skeletal changes. In ad - dition, a growing body of evidences demon - countries, especially in elderly men. Its preva - strates that uric acid might play a pathophysio - lence is growing also in other parts of the world, logical role in many “cardio-nephro-metabolic” such as New Zealand, where it reached 6 .4% in disorders, which seems to be independent of the 1992 3, or Eastern China, where it reached 1.14% deposition of monosodium urate crystals, since in 2008 4. More recently a nationwide population- it is evident also for serum uric acid concentra - based study by Trifirò et al 5 described an increase tions below the saturation point for monosodium urate. Taken together, these findings strongly of the prevalence of gout in Italy from 0.7% in suggest to carefully reconsider the concept of 2005 to 0.9% in 2009, with a male/female ratio “asymptomaticity” for chronic hyperuricemia of 4:1. A parallel trend towards an increasing and to consequently revise the normal range of prevalence of hyperuricaemia (serum uric acid > serum uric acid levels also considering the pro - 6 mg/dL) was also observed (8.5% in 2005 vs gressive worldwide increase of circulating levels 11.9% in 2009). However, the prevalence of hy - of uric acid, which could lead to a “shift to right” peruricaemia in Italian people was lower than in (i.e. toward higher values) of normal range. In the light of the new scientific knowledge on the other countries; indeed, epidemiological data pathophysiological role of uric acid in human showed an estimated prevalence of hyperuri - disease, a threshold value < 6.0 mg/dL (< 360 caemia of 21% in the US general population 6,

Corresponding Author: Giovambattista Desideri, MD; e-mail: [email protected] 1295 G. Desideri, G. Castaldo, A. Lombardi, M. Mussap, A. Testa, R. Pontremoli, L. Punzi, C. Borghi while population-based studies reported a preva - generation of uric acid 10 . About two-thirds of the lence ranging from 13% to 25% in China 2,4 . This uric acid produced daily are eliminated in the worldwide rise in the prevalence of hyper - kidney , while about a third is eliminated in the uricemia and gout may be related to the epidemic gastrointestinal tract due to the activity of intesti - diffusion of overweight and obesity 7, as well as nal bacteria 14 . In human kidney, urate handling the increased consumption of foods rich in involves urate glomerular filtration followed by a purines 8, alcohol 9, and soft drinks sweetened complex array of reabsorptive and secretory with fructose 10,11 . As a consequence, the mean mechanisms taking place in the proximal serum uric acid levels in United States is in - tubule 17 . Due to its water solubility and low affin - creased from 3.4 mg/dL in 1920s 12 to 6.25 mg/dL ity for plasma proteins urate is freely filtered by in 1970s 13 . This implies that perhaps it might be the glomerulus. At least 90% of the filtered uric more appropriate to define the reference range of acid undergoes active reabsorption in the proxi - serum uric acid levels according to its physiolog - mal tubule , and this process is mediated by spe - ical role and pathophysiological involvement in cific anion transporters , including URAT1 14,17-19 . human diseases , rather than according to the dis - This uric acid transporter, localized on the apical tribution of its circulating levels in the general side of proximal tubule cells, is an important de - population . terminant of the reabsorption of uric acid and is the target of uricosuric drugs such as probenecid, Metabolism of Uric Acid sulfinpyrazone and losartan 18,19 . The net result of Uric acid is the final product of endogenous these processes is the elimination in the urine of and dietary purine metabolism. Uric acid is a 7-12% of the filtered load. Chronic treatment weak acid with pKa of 5.75 in the blood and 5.25 with diuretics can reduce urate excretion , proba - in the urine. At a physiological pH of 7.4 in the bly through an increased reabsorption in the extracellular compartment the reaction uric acid proximal tubule secondary to volume depletion + ↔ urate H is shifted to the right; so the majority and/or a competition of diuretics with uric acid of uric acid (about 98%) circulates in the blood for secretory mechanisms at the level of the prox - as ionised urate. Because of the high concentra - imal tubule 20 . This anti-uricosuric effect of di - tion of sodium in the extracellular compartment, uretics seems to be evident only at doses > 25 urate is largely present as monosodium urate, mg/day 20 . Less than 10% of cases of hyper - with a low solubility limit of about 6 mg/dL (360 uricemia is due to hyperproduction , while the al - µmol/L )14,15 . When urate concentration exceeds most totality of cases is due to reduced excre - this limit the risk of monosodium urate crystal tion 14,15,21 . Patients with gout due to increased in - formation and precipitation increases. In urine, take of foods rich in purines are generally poor which is acidified along the renal tubule, urate is excreter , since they need urate concentrations converted into the less soluble uric acid 14,15 . Diet 120 -180 µmol/L higher than subjects without urate content is generally rather modest (100-200 gout to achieve similar uric acid excretion rates 22 . mg/day ), whereas endogenous uric acid mostly derives from de novo synthesis and catabolism of Biological Ambivalence of Uric Acid nucleic acids (500-600 mg/day )14 . Endogenous Uric acid was initially considered an inert urate is mainly produced in the liver and to a waste product of purine metabolism able to crys - lesser extent in the small intestine. Its production tallize at high concentrations , causing gouty depends on the balance between purine inges - arthritis and renal stones 14 . Recent scientific evi - tion, intracellular de novo synthesis, recycling, as dences demonstrated that uric acid exerts differ - well as xanthine oxidase function at the end of ent biological effects , depending on its chemical the purine pathway 16 . A relevant cause of over - microenvironment, including a protective antiox - production of urate in Western countries is repre - idant activity as well as a dangerous pro-oxidant sented by an excess of fructose consumption 10 . action 17 . Uric acid alone contributes to about half This sugar is the substrate of the enzyme fructok - of the antioxidant capacity of human plasma and inase , which generates fructose-1-phosphate by a its antioxidant properties are comparable to those process in which a molecule of ATP is consumed of ascorbic acid 23 . This molecule is capable of and a molecule of ADP and organic phosphate preventing the nitrosylation of proteins induced are generated. This enzymatic reaction is almost by peroxynitrite, the peroxidation of lipids and irreversible : ATP is not regenerated while ADP is proteins, the inactivation of tetrahydrobiopterin, converted to AMP, which is a substrate for the an essential cofactor of nitric oxide synthase, and

1296 Is it time to revise the normal range of serum uric acid levels? the Cu 2+ -mediated LDL oxidation 17 . Uric acid al - so can not regulate these levels effectively 37,38 . As so has the ability to prevent degradation of the a consequence, circulating levels of uric acid in extracellular superoxide dismutase, a critical en - the general population are continuously increas - zyme in defending cells from superoxide anion ing and are nowadays quite higher compared to toxicity 24 . Uric acid can also help to preserve those observed in primates lacking uricase , who sodium retention and blood pressure 25 and, thus, have serum uric acid levels typically in the 3 -4 might have played a role in accelerating the de - mg/dL range 38 . In addition, uric acid levels in the velopment of bipedal locomotion during an evo - primitive Yanomamo of southern Venezuela , lutionary period in which food was probably whose life conditions were likely similar to those scarce and sodium intake low 26,27 . In addition, of our prehistoric ancestors , averaged only uric acid might contribute to the development of around 3 mg/dL , suggesting that primitive hu - insulin resistance and mild obesity 28 , through its mans had lower uric acid levels than today 27 . In ability to interfere with some actions of insulin modern age subjects who achieve the highest uric by reducing endothelial nitric oxide , as well as to acid levels and develop hypertension, insulin re - directly act on the adipocyte 29,30 , thereby favoring sistance, diabetes mellitus , obesity, and cardio - survival during a period of famine or stress. Fi - vascular diseases 37 seem to have lost the evolu - nally, the increase of serum urate concentration tionary advantage deriving from uricase gene si - might also have lead to an improvement in reac - lencing . Thus, due to the marked changes in diet tion time and mental performance that helped resulting in a dramatic increase in purine- and man evolution 31,32 , or to an amelioration of innate fructose-rich fooods, increase of serum uric acid immune function and the ability to ward off in - levels could represent the expression of a physio - fections or tumors 33,34 . This intriguing hypothesis logical adaptation gone awry in Western of a survival advantage deriving from increased societies 27 . circulating levels of uric acid is in contrast with the growing bulk of data suggesting a pathophys - Uric Acid and Muscoloskeletal Damage iological role of this molecule in human diseases. Gout is the most common inflammatory arthri - In addition to the well known link between hype - tis in men , although it is often misdiagnosed or ruricemia and gout, a growing body of evidences recognized late in its clinical course, expecially suggests that hyperuricemia can possibly lead to in elderly subjects , in whom its clinical manifes - cardiovascular, renal and metabolic dysfunc - tations may be attributed to osteoarthritis 39 . The tion 15,35 . From a pathophysiological perspective, pathophysiology of gout includes, in the pres - in vitro and cellular studies demonstrated that , ence of hyperuricaemia, the intra-articular depo - depending on the chemical microenvironment, sition of monosodium urate crystals , which is re - uric acid may exert pro-oxidant or nitric oxide- sponsible for the onset of acute attacks of inflam - reducing effects that may explain the association matory arthritis, possibly leading to chronic among hyperuricemia, hypertension, metabolic arthropathy 14 . Although the formation of syndrome, and cardiovascular diseases 35 . Thus, monosodium urate crystals in joint fluids mainly uric acid is a molecule with extremely complex depends on the local concentration of urate , it is metabolic and biochemical effects that can not be also influenced by other factors , including articu - simplistically divided into beneficial or harmful lar hydration state, temperature, pH and presence regardless of its microenvironment and, above of extracellular matrix proteins such as proteo - all, its concentrations in biological fluids 17 . Taken glycans and collagens 14,40 . Most often monosodi - together scientific evidences suggest a sort of um urate crystals are released from preformed “collision” between the trajectory of genetic evo - deposits in the joints and are coated by protein or lution and that of social evolution in the modern polypeptide molecules including IgG antibodies era , mainly because of the shifts in dietary habits that facilitate phagocytosis 14,40 . Protein adsorp - brought about by increasing prosperity during the tion is not, however, an indispensable step for last few decades . In today’s societies people con - cellular activation, as crystals are able to directly sume significantly more meat and fructose , interact with monocyte cell membranes as parti - which both generate uric acid. On the other hand , cles 14,40 . After phagocytosis, crystals activate the as a consequence of the uricase mutation which NALP3 inflammasoma, a cytoplasmic complex occurred in humans and higher primates in mid consisting of intracellular immune receptors, thus Miocene 36 , humans not only have higher uric triggering a typical inflammatory response acid levels than most other mammals , but they al - through release of pro-inflammatory mediators ,

1297 G. Desideri, G. Castaldo, A. Lombardi, M. Mussap, A. Testa, R. Pontremoli, L. Punzi, C. Borghi such as interleukin 1 β and tumour necrosis factor the value of 6 mg/dL results in elimination of α which in turn, by interacting with specific re - gout flares and improvement of tophus status ceptors expressed on synoviocytes, lead to the over time 54 . These observations are of great clini - production of chemokines and the accumulation cal relevance , requiring to carefully reconsider of neutrophils in the joint 41 . The classic gout flare the management of asymptomatic chronic hyper - usually develops after years of asymptomatic hy - uricemia : although chronically elevated serum peruricemia , which represents a possible harbin - urate has not usually been considered to play a ger of clinical gout, being the incidence of gout pathogenetic role in tissue damage , the ultra - directly correlateed to the degree of hyperuri - sound evidences reported above might warrant caemia 42 . Furthermore , monosodium urate depo - the use of urate-lowering agents also in patients sition was demonstrated to occur in any body flu - with persistent hyperuricemia without clinical id with a urate level > 6.8 mg/dL 43 , and signs of gout 47 . monosodium urate crystals were detected in asymptomatic joints of patients with gout 44 . The Uric Acid and Traditional Cardiovascular presence of monosodium urate crystals in the Risk Factors synovial fluid from asymptomatic individuals During the last few decades several epidemio - with hyperuricemia has been demonstrated by logical studies have reported a relation between means of polarized light microscopy since early serum uric acid levels and traditional cardiovas - 1980s 45 . Silent deposition of monosodium urate cular risk factors , including hypertension , meta - crystals as a result of hyperuricaemia may lead to bolic syndrome and diabetes mellitus , suggesting early destructive skeletal changes : a large per - a possible pathophysiologic link between these centage of patients with gout and normal radi - conditions 55 . In humans , hyperuricaemia is asso - ographs have occult destructive arthropathy de - ciated with an increased risk of incident hyper - tectable by advanced imaging , such as MRI tension, which is independent of traditional risk and/or ultrasound 46 . Interestingly , ultrasound factors and more pronounced in younger individ - evaluation can identify a wide spectrum of sub - uals with pre-hypertension and in women 56,57 . On clinical morphostructural changes suggestive of the other hand, treatment with allopurinol of ado - gouty arthritis in both intra- and extra-articular lescents with hypertension and hyperuricemia structures in asymptomatic individuals . Pineda et was reported to be associated with a significant al 47 recently described the typical hyperechoic reduction compared to placebo in systolic (−6.9 enhancement of the superficial margin of hyaline ± 4.4 mm Hg vs −2.0 ± 0.4, p = 0.007) and dias - cartilage (double contour sign) in 25% of the first tolic (−5.1 ± 2.4 mmHg vs −2.4 ± 0.7, p = 0.03) metatarsophalangeal joints and in 17% of the blood pressure 58 . Interestingly, the threshold val - femoral cartilage of hyperuricemic asymptomatic ue of serum uric acid associated with hyperten - individuals (vs 0% in the control group ). Patellar sion seems to be as low as 5.0-5.5 mg/dL, clearly and Achilles enthesopathy were also more fre - below its supersaturation value, thus being prob - quent in hyperuricemic than in normouricemic ably independent of the formation of monosodi - individuals (12% versus 2.9%; p = 0.01 and 15% um crystals 56 . In adolescents with newly diag - versus 1.9%, p = 0.0007 respectively) . The dou - nosed, never treated stage 1 essential hyperten - ble contour sign has been described in gout only, sion and serum uric acid levels > 6 mg/dL , reduc - and reflects the preference of serum urate to tion of uric acid levels to values < 5 mg/dL with crystallize on the surface of cartilage 48,49 . As con - allopurinol therapy was associated with blood firmation of the presence of monosodium urate in pressure normalization in 86% of patients, as the hyaline cartilage , the double contour sign dis - compared with 3% with placebo 58 . appears in patients with gout successfully treated An elevated serum urate concentration is com - with urate-lowering agents, maintaining serum monly associated with other components of the urate levels below the solubility limit of uric acid metabolic syndrome as well 59 . Although the in - (< 6 mg/dL) for at least 7 months 50 . Accordingly, crease in serum urate has often been considered the primary therapeutic goal of urate lowering to be secondary, recent evidences suggest that it therapy, i.e. promoting crystal dissolution and may play a pathophysiological role in glucose preventing crystal formation , is achievable by dysmetabolism 55 . Elevated serum urate levels maintaining serum uric acid levels below the sat - commonly precede insulin resistance, type 2 dia - uration point for monosodium urate 51-53 . Long betes mellitus 60,61 , and obesity 62 , and studies in term maintenance of serum uric acid levels below cell cultures and animal models have suggested a

1298 Is it time to revise the normal range of serum uric acid levels? causative role for urate in the pathogenesis of the serum uric acid > 7 mg/dL compared to women metabolic syndrome. A recent metanalysis of 7 with a serum uric acid < 4 mg/dL 66 . The relation - eligible articles derived from 8 prospective co - ship between serum uric acid levels and cardio - hort studies, involving a total of 32 ,016 partici - vascular events is also evident for moderately in - pants and 2930 incident cases of type 2 diabetes , creased levels of uric acid or for values corre - provided strong evidence that high levels of sponding to the upper limit of the actual normal serum uric acid are a risk factor for developing range, as well as for patients with preexisting type 2 diabetes in middle-aged and older people, cardiovascular disease. In the Preventive Cardiol - independent of other established risk factors, es - ogy Information System (PRECIS) Database Co - pecially metabolic syndrome components 63 . In - hort Study uric acid levels were significantly terestingly, the presence of only moderately in - higher in patients with a diagnosis of coronary creased serum uric acid levels (> 5.3 mg/dL in artery disease than in individuals with no history women and > 7.0 mg/dL in men) is also associat - of cardiovascular disease (6.3 ± 1.7 mg /dL ver - ed with a significantly increased risk of develop - sus 5.9 ± 1.6 mg/dL, p < 0.001) 67 . After 3 year of ing type 2 diabetes mellitus (hazard ratio: 2.78, follow-up , a 39% increased risk of all-cause mor - 95% CI: 1.35-5.70, p = 0.0054) 64 . Pathophysio - tality (95% CI: 1.28-1.50 p < 0.001) was evident logical mechanisms underlying this association for each mg/dL increase in serum uric acid 67 . likely include a hyperuricaemia-induced en - Similarly, in patients with moderate-to-severe dothelial dysfunction, leading to reduced insulin- heart failure increased levels of serum uric acid stimulated nitric oxide-induced vasodilatation were associated with a worse prognosis , with a and decreased glucose uptake in skeletal muscle, linear relationship between uric acid levels and as well as inflammatory and oxidative changes probability of death 68 . The presence of deposits induced by intracellular urate levels in of urate crystals represents an important determi - adipocytes 35,55 . nant of increased cardiovascular risk in patients Taken together , these findings suggest a patho - with gout . Data from the screening program con - physiological relationship between serum uric ducted in Chang Gung Memorial Hospital in Tai - acid and traditional cardiovascular risk factors wan from 2000 to 2006 clearly indicate that the which probably starts below the upper threshold risk of fatal cardiovascular events was signifi - value of serum uric acid currently considered as cantly higher in hyperuricaemic patients with normal in many countries . gout (HR : 1.97, 95% CI: 1.08-3.59) compared to subjects without gout (HR : 1.08, 95% CI: 0.78- Uric Acid and Cardiovascular Diseases 1.51) 69 . Similarly, in the Multiple Risk Factor In - Epidemiological data support a strong associa - tervention Trial (MRFIT ) patients with gout tion between gout, hyperuricemia and cardiovas - showed a higher risk of coronary events (HR cular diseases . The analysis of data from 5926 1.35, 95% CI: 1.06-1.72) , mortality from my - U.S. participants in the National Health and Nu - ocardial infarction (HR: 1.35, 95% CI: 0.94- trition Survey (NHANES I) after a mean follow- 1.93) , cardiovascular mortality (HR: 1.21, 95% up of 16.4 years showed a positive relationship CI: 0.99-1:49 ) and all-cause mortality (HR: 1.09, between increased levels of uric acid and cardio - 95% CI: 1.00-1.19) compared to subjects without vascular mortality; for each mg/dL increase in gout (p = 0.04) 70 . More recently , the Health Pro - serum uric acid , cardiovascular mortality in - fessionals Follow-up Study confirmed the ad - creased by 9% in men (HR : 1.09, 95% CI: 1.02- verse prognostic impact of chronic deposition of 1.18) and 26% in women (HR : 1.26, 95% CI: urate , demonstrating an increased risk of total 1.16-1.36) 65 . Interestingly, the increased risk of mortality (RR 1.28, 95% CI: 1.15-1.41 ) and fatal fatal cardiovascular events associated to elevated coronary events (RR: 1.38, 95% CI: 1.15-1.66 ) in serum uric acid levels was especially evident in individuals with a history of gout 71 . These pa - older individuals at enrollment 65 , suggesting that tients also had an increased risk of nonfatal my - hyperuricemia must persist for a relatively long ocardial infarction compared to individuals with - time to cause vascular injury , as also observed out gout (RR: 1.59, 95% CI: 1.04-2.41) 71 . Ac - for traditional cardiovascular risk factors. These cording to these findings , Stack et al 72 recently findings confirm previous observations in the described an independent association of gout and same population during a survey of shorter dura - serum uric acid with total and cardiovascular tion, demonstrating a mortality from ischemic mortality. In particular, mortality risks associated heart disease 5 times higher among women with with gout and high serum uric acid levels were

1299 G. Desideri, G. Castaldo, A. Lombardi, M. Mussap, A. Testa, R. Pontremoli, L. Punzi, C. Borghi determined for 15 ,773 participants, aged 20 years drug. These results were recently confirmed by a or older, in the Third National Health and Nutri - Scottish study that showed a significant reduction tion Examination Survey , by linking baseline in - in the risk of cardiovascular events (HR: 0.69, formation collected between 1988 and 1994 with 95% CI: 0.50-0.94 ) and mortality (HR: 0.75, mortality data up to 2006. Compared with sub - 95% CI: 0.59- 0.94) in patients treated with allop - jects without a history of gout, the multivariable urinol 300 mg/day compared to those assuming hazard ratio for subjects with gout were 1.42 (CI : 100 mg/day of the same drug 78 . 1.12- 1.82) for total and 1.58 (CI : 1.13- 2.19) for cardiovascular mortality. Adjusted hazard ratios Uric Acid and Brain Health for each mg/dL increase in uric acid were 1.16 Increased circulating levels of uric acid have (CI : 1.10- 1.22) for total and cardiovascular mor - been proposed as an evolutionary advantage for tality and this pattern was consistent across dis - early hominoids due to its potential neurostimu - ease categories. In the conjoint analysis, the ad - lant properties , based on its chemical similarty to justed hazard ratios for mortality in the highest caffeine 31 . Several studies described relationships two uric acid quartiles were 1.64 (CI : 1.08- 2.51) between uric acid levels and IQ testing 79, achieve - and 1.77 (CI : 1.23- 2.55), respectively, for sub - ment-oriented behavior 80 , and school jects with gout, and 1.09 (CI : 0.87- 1.37) and 1.37 performance 81, although these associations were (CI : 0.11- 1.70), respectively, for subjects without generally weak. Despite the intriguing hypothesis gout, compared with those without gout in the that uric acid might have neuroprotective proper - lowest quartile. Interestingly, three of the four ties, elevated serum uric acid levels are also asso - quartiles of serum uric acid considered in this ciated with conditions that increase the risk of study were identified by serum uric acid intervals cognitive dysfunction. Older adults with high nor - below the threshold of 6 mg/dL (first quartile < mal concentrations of serum uric acid are 2.7 to 4.3, second 4.3-5.2, third 5.2-6.0 and fourth > 6.0 5.9 times more likely to score in the bottom quar - mg/dL) 72 . These findings are in complete agree - tile for measures of processing speed, verbal ment with previous data suggesting that the rela - memory, and working memory even after adjust - tion between uric acid and cardiovascular disease ment for potential confounding factors such as is evident not only in the presence of overt hyper - age, sex, race, education, diabetes, hypertension, uricemia but also with serum uric acid levels smoking, and alcohol intake 82 . Similarly, in pa - considered in the normal to high range (> 5.2 to tients with chronic kidney disease, defined by a 5.5 mg/dL )55,73,74 . The close relationship between glomerular filtration rate < 60 mL/min/1.73 m 2, hyperuricemia and cardiovascular events is con - an independent association between circulating firmed by some interesting evidences suggestive levels of uric acid and reduced cognitive perfor - of a reduction in the probability of developing mance (r: -0 297, p < 0.0001) was described 83 . cardiovascular events associated with the reduc - Furthermore, in the InChianti study, which in - tion of serum uric acid levels . A post-hoc analy - cluded a cross-sectional assessment of circulating sis of data from the Reduction of Endpoints in levels of uric acid and cognitive performance in type 2 diabetes with the Angiotensin II Antago - 1016 community-dwelling elderly subjects, de - nist Losartan (RENAAL ) study demonstrated mented patients had higher uric acid levels (5.75 that each 0.5 mg/dL decrease of serum uric acid ± 1.90 vs 5.13 ± 1.35 mg/dL, p < 0.001) and the observed in the first 6 months of treatment, due prevalence of subjects affected by dementia in - to the ability of losartan to interfere with renal re - creased across uric acid tertiles ( p < 0.0001) 84 . absorption of uric acid thus enhancing renal ex - Even after adjustment for possible confounding cretion , was associated with a 5.3% reduction in factors , the highest tertile of serum uric acid was the risk of cardiovascular events ( 95% CI: 0.9- associated with a threefold risk for dementia (OR 9.9, p = 0.017) 75 . This finding suggests the possi - = 3.32, 95% CI: 1 .06 to 10 .42), while the interme - bility that increased levels of uric acid may repre - diate tertile was associated with a higher proba - sent a modifiable cardiovascular risk factor, at bility of dementia than the lowest tertile. Interest - least in diabetic patients with renal disease. In ingly, the relationship between circulating levels line with these findings is the demonstration of a of uric acid and dementia was already evident for better cardiovascular prognosis in patients with levels of uric acid essentially below its solubility heart failure 76 or diabetes mellitus 77 treated with limit 84 . These findings suggest that the effect of high doses of allopurinol compared to those uric acid on cognitive function does not depend treated with lower doses of this urate lowering on the precipitaion of monosodium urate crystals.

1300 Is it time to revise the normal range of serum uric acid levels?

In this regard, Schretlen et al 85 demonstrated that impairs the renal autoregulatory response and adults with high normal serum uric acid levels are thereby causes glomerular hypertension 91 . In hu - 2.8 times more likely to show greater than aver - mans a number of cross-sectional studies found age white matter hyperintensity burden , which an association between urate levels and de - likely mediates the relationship between serum creased estimated glomerular filtration rate or uric acid and cognitive dysfunction. In another in - microalbuminuria, although the interpretation of teresting work 86 by the same group performed in these findings is difficult, since chronic kidney community-dwelling adults aged 20 to 96 years, disease can elevate urate levels, and hyperuri - serum uric acid was significantly associated with caemia might cause or aggravate chronic kidney greater white matter hyperintensities and poorer disease . Focusing on incident chronic kidney dis - working memory, processing speed, fluency, and ease, most studies showed an independent associ - verbal memory. Associations persisted after con - ation with serum urate levels. However, the trolling for age, sex, race, education, hyperten - analysis of the progression of chronic kidney dis - sion, diabetes, alcohol abuse, smoking, and body ease and its relationship to urate levels gave con - mass. The addition of a term for white matter hy - flicting results, most studies finding no indepen - perintensity attenuated these associations , in that dent association with hyperuricaemia. This could uric acid no longer predicted cognitive perfor - indicate that urate is a risk factor for the onset of mance 86 . Taken together these findings indicate chronic kidney disease more than for its progres - that severity of cerebral ischemia might mediate sion 92 . However, a recent review supports the role the association between uric acid and cognitive of urate as a risk factor for chronic kidney dis - dysfunction. Even more interestingly, circulating ease 93 . The evidence that the reduction of serum levels of serum uric acid in this study population uric acid concentration might favorably affect the were quite low (4.5 ± 1.4 mg/dL) 86 . Thus, also clinical course of kidney disease further supports mild elevations in uric acid appear to contribute to the hypothesis of a detrimental role or uric acid structural and functional brain changes. A grow - on renal function. Siu et al 94 demonstrated that 12 ing body of evidence indicates that serum uric months allopurinol treatment decreased systolic acid is also an independent predictor of stroke 87 . blood pressure (from 140 to 127 mmHg) and Storhaug et al 88 recently demonstrated in a 12-15 slowed chronic kidney disease progression . year prospective study on 5700 men and women Goicoechea et al 95 described a favorable effect of free of diabetes and cardiovascular diseases, that allopurinol on estimated glomerular filtration rate each 1 SD (1.5 mg/dL) increase in serum uric decline (defined as a decrease of > 0.2 acid was associated with a 22% increased risk for mL/min/1.73 m 2; adjusted HR : 0.53) and a bene - ischemic stroke and a 13% increased risk for all- ficial effect on cardiovascular endpoints (7/57 cause mortality. Taken together, the above data in - versus 15/56), but no effect on blood pressure . dicate that serum uric acid might have a detrimen - Momeni et al 96 described a reduction in protein - tal impact on brain vasculature and consequente - uria (from 1.8 to 1.0 versus 1.7 to 1.6 g /24 h ) af - ly, on brain structure and function . ter allopurinol treatment in patients with type 2 diabetes mellitus and diabetic nephropathy. In Uric Acid and Renal Disease IgA nephropathy patients Shi et al 97 described a Experimental studies suggest the possibility reduction of the antihypertensive drug doses in that an elevated concentration of uric acid itself 7/9 cases with hypertension during 6 months al - can lead to kidney disease without the deposition lopurinol treatment versus 0/9 in the control of uric acid crystals 89,90 . Animal studies demon - group . In a posthoc analysis of the Reduction of strated that experimental hyperuricaemia ob - Endpoints in type 2 diabetes with the An - tained through inhibition of uricase can cause de giotensin II Antagonist Losartan (RENAAL ) tri - novo kidney disease , as well as accelerate exist - al, losartan reduced urate levels by 0.16 mg/dL ing renal dysfunctions 89,90 . The main lesions from 6.7 mg/dL during the first 6 months; adjust - caused by increased uric acid in the rat are ment for the urate effect indicated that 1/5 of glomerulosclerosis, interstitial fibrosis, and arte - losartan renoprotective effects could be attributed riolar disease, conditions similar to those ob - to this reduction in urate 98 . Taken together , the served in “gouty” nephropathy, except for the ab - above findings suggest an influential role of sence of intrarenal urate crystals 89,90 . The mecha - serum uric acid on renal function , which likely nism of injury appears to be related to the devel - starts below its solubility limit , being indepen - opment of preglomerular arteriolar disease that dent of monosodium urate crystals deposition .

1301 G. Desideri, G. Castaldo, A. Lombardi, M. Mussap, A. Testa, R. Pontremoli, L. Punzi, C. Borghi

Is it Time To Revise the Upper Threshold seems to better identify true “healthy subjects ”. for Serum Uric Acid Levels? Moreover, from an analytical perspective, con - In health-related fields, a reference range sidering that desirable analytical goals for im - usually describes the variations of a measure - precision and bias should be 4.3% and 4.8%, re - ment or value in healthy individuals. In particu - spectively 99 , for a threshold of serum uric acid lar, the standard definition of a reference range concentration of 6.0 mg/dL the imprecision for a particular measurement is defined as the should not exceed 0.26 mg/dL, giving a range predicted interval including 95% of values of a of uncertainty between 5.74 and 6.26 mg/dL, reference group, in such a way that in 2.5% of i.e. substantially below the solubility limit of cases a sample value will be smaller than the uric acid. Therefore, in the light of the new sci - lower limit of this interval, and in 2.5% of cases entific knowledge on hyperuricemia, the recom - it will be larger than the upper limit of this in - mendable upper threshold value for serum uric terval, whatever the distribution of these values. acid should reasonably be considered < 6.0 By this approach , serum uric acid values be - mg/dL. This methodological approach could tween 3.5 and 7.2 mg/dL in adult males and represent also a strategy to sensitize clinicians postmenopausal woman and between 2.6 and towards clinical problems now recognized to be 6.0 mg/dL in premenopausal women have been related to uric acid . identified as normal in many countries. Howev - er, epidemiological and experimental data accu - mulated during the last few decades suggest that Conclusions this methological approach to identify reference range could present some weaknesses when ap - Gout is one of the earliest disorders recog - plied to serum uric acid levels. Indeed, epidemi - nised as a clinical entity , which has been associ - ological data suggest a progressive worldwide ated since its first description to a state of socio- increase of circulating levels of uric acid , which economic welfare . During the last years , gout could lead to a “shift to right” (i.e. toward high - has gained renewed interest by clinicians mainly er values) of normal range. Thus, it seems rea - because its continously increasing prevalence , sonable to redefine the normal threshold values which is likely to be greater than the epidemiol - of uric acid according to its physiological role ogy of “podagra” could suggest. Indeed, radio - and its pathophysiological involvement in hu - logical evidences demonstrate a wide spectrum man diseases. Regarding the target population, of subclinical morphostructural skeletal changes , healthy subjects are likely to be represented by suggesting that articular damage induced by hy - individuals without clinical evidence of gout. peruricemia can occur in both intra- and extra- However, a number of evidences suggest that articular structures in asymptomatic individuals. articular damage may occur also without clini - These data open a new battlefront in the current cal evidence of acute artritis. In addition, the debate about the opportunity to maintain serum growing body of evidences presented above uric acid levels below the threshold value of 6.0 suggests that serum uric acid might also exert a mg/dL (360 µmol/L ) also in these subjects as al - detrimental influence on cardiovascular system, ready recommended for patients with overt brain and kidney and negatively influence glu - gouty arthritis 51- 53 . In addition, a growing body cose metabolism. Interestingly, this influence of evidences demonstrates that uric acid might seems to be evident also for circulating levels of play a pathophysiological role in many “cardio- uric acid below its saturation limit , indicating nephro-metabolic” disorders, which seems to be that it is likely independent of precipitation of independent of the deposition of monosodium urate monosodium crystals. Thus, the defintion urate crystals , since it is evident also for serum of normal range of serum uric acid in the gener - uric acid concentrations below the saturation al population is inevitably influenced by what point for monosodium urate. Taken together , we consider as “normal” , since the absence of these findings strongly suggest to carefully re - gout flares does not necessarily imply the ab - consider the concept of “asymptomaticity” for sence of uric acid related damage. On the other chronic hyperuricemia and to consequently re - hand, there are also “optimal health ranges” vise the normal range of serum uric acid levels. identifying the optimal health impact on people. A threshold value for serum uric acid < 6.0 This might be the case for uric acid , since a mg/dL (< 360 µmol/L) should reasonably be threshold value < 6.0 mg/dL (< 360 µ mol/L ) considered for all subjects.

1302 Is it time to revise the normal range of serum uric acid levels?

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