Renal Transport of Uric Acid: Evolving Concepts and Uncertainties
2012; Elsevier BV; Volume: 19; Issue: 6 Linguagem: Inglês
10.1053/j.ackd.2012.07.009
ISSN1548-5609
AutoresI. Alexandru Bobulescu, Orson W. Moe,
Tópico(s)Case Reports on Hematomas
ResumoIn addition to its role as a metabolic waste product, uric acid has been proposed to be an important molecule with multiple functions in human physiologic and pathophysiologic processes and may be linked to human diseases beyond nephrolithiasis and gout. Uric acid homeostasis is determined by the balance between production, intestinal secretion, and renal excretion. The kidney is an important regulator of circulating uric acid levels by reabsorbing about 90% of filtered urate and being responsible for 60% to 70% of total body uric acid excretion. Defective renal handling of urate is a frequent pathophysiologic factor underpinning hyperuricemia and gout. Despite tremendous advances over the past decade, the molecular mechanisms of renal urate transport are still incompletely understood. Many transport proteins are candidate participants in urate handling, with URAT1 and GLUT9 being the best characterized to date. Understanding these transporters is increasingly important for the practicing clinician as new research unveils their physiologic characteristics, importance in drug action, and genetic association with uric acid levels in human populations. The future may see the introduction of new drugs that act specifically on individual renal urate transporters for the treatment of hyperuricemia and gout. In addition to its role as a metabolic waste product, uric acid has been proposed to be an important molecule with multiple functions in human physiologic and pathophysiologic processes and may be linked to human diseases beyond nephrolithiasis and gout. Uric acid homeostasis is determined by the balance between production, intestinal secretion, and renal excretion. The kidney is an important regulator of circulating uric acid levels by reabsorbing about 90% of filtered urate and being responsible for 60% to 70% of total body uric acid excretion. Defective renal handling of urate is a frequent pathophysiologic factor underpinning hyperuricemia and gout. Despite tremendous advances over the past decade, the molecular mechanisms of renal urate transport are still incompletely understood. Many transport proteins are candidate participants in urate handling, with URAT1 and GLUT9 being the best characterized to date. Understanding these transporters is increasingly important for the practicing clinician as new research unveils their physiologic characteristics, importance in drug action, and genetic association with uric acid levels in human populations. The future may see the introduction of new drugs that act specifically on individual renal urate transporters for the treatment of hyperuricemia and gout. Clinical Summary•Uric acid or urate may have multiple physiologic roles, including blood pressure regulation, immune modulation, and antioxidation/pro-oxidation balance.•Hyperuricemia has been associated with prevalent diseases, including hypertension, metabolic syndrome, and chronic kidney disease, but whether uric acid has a causal role in the pathogenesis of these conditions is not yet known.•Renal handling of urate has a pivotal role in uric acid homeostasis and is achieved through a complex interplay of reabsorption and secretion, primarily in the proximal tubule; urate transport is unlikely to follow the classic 4-component model of filtration, presecretory reabsorption, secretion and postsecretory reabsorption, although this model is still perpetuated at times in the literature.•Of the multiple transport proteins that may play a role in renal transport of urate, the best characterized to date are apical URAT1 and basolateral GLUT9, both with demonstrated effects on uric acid levels and direct regulation by known uricosuric drugs; these transporters present attractive targets for current and future drug development. •Uric acid or urate may have multiple physiologic roles, including blood pressure regulation, immune modulation, and antioxidation/pro-oxidation balance.•Hyperuricemia has been associated with prevalent diseases, including hypertension, metabolic syndrome, and chronic kidney disease, but whether uric acid has a causal role in the pathogenesis of these conditions is not yet known.•Renal handling of urate has a pivotal role in uric acid homeostasis and is achieved through a complex interplay of reabsorption and secretion, primarily in the proximal tubule; urate transport is unlikely to follow the classic 4-component model of filtration, presecretory reabsorption, secretion and postsecretory reabsorption, although this model is still perpetuated at times in the literature.•Of the multiple transport proteins that may play a role in renal transport of urate, the best characterized to date are apical URAT1 and basolateral GLUT9, both with demonstrated effects on uric acid levels and direct regulation by known uricosuric drugs; these transporters present attractive targets for current and future drug development. Although gout and kidney stones were recognized in antiquity,1Nuki G. Simkin P.A. A concise history of gout and hyperuricemia and their treatment.Arthritis Res Ther. 2006; 8: S1Crossref PubMed Scopus (239) Google Scholar the earliest known description of uric acid dates from the year of the American Declaration of Independence, when German-Swedish chemist Karl Wilhelm Scheele (1742-1786) isolated a substance with acidic properties from a bladder stone and named it "lithic acid" (from Greek "lithos," meaning stone).2Richet G. The chemistry of urinary stones around 1800: a first in clinical chemistry.Kidney Int. 1995; 48: 876-886Crossref PubMed Scopus (23) Google Scholar George Pearson (1751-1828) and Antoine Fourcroy (1755-1809) later changed the name from "lithic" to "uric," to reflect the presence of this substance in normal urine and its absence from some calculi.3Thomson T. Chemistry of Animal Bodies. 1858: Edinburgh, UK: 31. Digitized version available at http://books.google.comGoogle Scholar Fast forward more than 230 years, and our current knowledge of uric acid and its relationship with living organisms, from single genes and molecules to human physiologic and pathophysiologic processes, could fill a massive treatise. However, several chapters of the uric acid story remain incomplete, with fundamental scientific questions still awaiting response. We will cover 2 aspects in this article. First, we provide a summary of the known and potential roles of uric acid in human physiologic and pathophysiologic processes on the backdrop of evolutionary physiology. Second, we discuss the mechanisms of uric acid transport in the kidney, the major regulator of uric acid levels in humans. Uric acid (2,6,8-trihydroxypurine [C5H4N4O3]) is the end-product of purine metabolism in humans, but it is an intermediary product in most other mammals. It is generated primarily in the liver (Fig 1) by the action of xanthine oxidase, a molybdenum metalloenzyme that can be inhibited pharmacologically by drugs like allopurinol and febuxostat.4Brondino C.D. Romao M.J. Moura I. Moura J.J. Molybdenum and tungsten enzymes: the xanthine oxidase family.Curr Opin Chem Biol. 2006; 10: 109-114Crossref PubMed Scopus (97) Google Scholar, 5Schlesinger N. New agents for the treatment of gout and hyperuricemia: febuxostat, puricase, and beyond.Curr Rheumatol Rep. 2010; 12: 130-134Crossref PubMed Scopus (22) Google Scholar Very little uric acid is normally ingested. Most circulating uric acid is freely filtered in the kidney, with roughly 90% of the filtered load normally reabsorbed along the nephron by mechanisms reviewed later in this article. Renal excretion of uric acid represents approximately 60% to 70% of total uric acid excretion from the body.6Maesaka J.K. Fishbane S. Regulation of renal urate excretion: a critical review.Am J Kidney Dis. 1998; 32: 917-933Abstract Full Text PDF PubMed Scopus (202) Google Scholar, 7Sorensen L.B. Levinson D.J. Origin and extrarenal elimination of uric acid in man.Nephron. 1975; 14: 7-20Crossref PubMed Scopus (106) Google Scholar A smaller proportion of uric acid is secreted in the intestine and is further metabolized by resident gut bacteria in a process termed intestinal uricolysis.7Sorensen L.B. Levinson D.J. Origin and extrarenal elimination of uric acid in man.Nephron. 1975; 14: 7-20Crossref PubMed Scopus (106) Google Scholar Uric acid is a weak diprotic acid (has 2 dissociable protons) with pKa1 ≈ 5.4 and pKa2 ≈ 10.3. At the physiologic pH of 7.4, a proton dissociates from approximately 99% of uric acid molecules, and thus most uric acid is present in the extracellular fluid as monovalent urate anion (also known as hydrogen urate or acid urate). The divalent urate anion is practically nonexistent in the body because of the very high pKa2, and thus the term urate is generally used to refer to monovalent urate in the biomedical literature. Because the ratio of urate to uric acid in the circulation remains constant with constant pH, the terms urate and uric acid are often used interchangeably to refer to the total pool of uric acid, dissociated and undissociated. In the urine, the ratio of uric acid to urate varies much more with the larger range of pH, and lower urinary pH values result in a greater proportion of uric acid in the undissociated form. Since undissociated uric acid is very poorly soluble in aqueous solutions, unduly acidic urinary pH values increase the propensity for uric acid crystallization and nephrolithiasis.8Sakhaee K. Adams-Huet B. Moe O.W. Pak C.Y. Pathophysiologic basis for normouricosuric uric acid nephrolithiasis.Kidney Int. 2002; 62: 971-979Crossref PubMed Scopus (264) Google Scholar In many organisms, including the majority of mammals, uric acid is metabolized to allantoin by the enzyme urate oxidase (uricase). Over a period of 20 to 30 million years during the evolution of primates, the uricase gene incurred several independent mutations in its promoter and coding regions, resulting in gradual loss of uricase function in the primate lineage. Modern humans and higher primates have nonfunctional uricase genes (pseudogenes) because of frameshift and missense mutations, and some New World and Old World monkeys harboring promoter mutations have decreased uricase activity compared with other mammals.9Oda M. Satta Y. Takenaka O. Takahata N. Loss of urate oxidase activity in hominoids and its evolutionary implications.Mol Biol Evol. 2002; 19: 640-653Crossref PubMed Scopus (305) Google Scholar Although not the main scope of this review, a brief exploration of the biological underpinnings of uricase inactivation is in fact important for understanding the role of uric acid in Homo sapiens and, by extension, for understanding the logic of urate handling in the kidney. Experimental inactivation of the uricase gene in mice leads to massive deposition of uric acid crystals in the kidney, obstructive nephropathy, and death, with most animals dying before sexual maturity.10Wu X. Wakamiya M. Vaishnav S. et al.Hyperuricemia and urate nephropathy in urate oxidase-deficient mice.Proc Natl Acad Sci U S A. 1994; 91: 742-746Crossref PubMed Scopus (236) Google Scholar By contrast, when nature experimented with loss of uricase function in early hominoids, the result was evolutionarily successful organisms. It is possible that uricase loss in our ancestors was perpetuated because higher uric acid levels provided some physiologic benefit. However, since higher uric acid can also cause harm in an organism not equipped to handle it (eg, the uricase-deficient mouse), it is also likely that with uricase loss other functionally related genes changed to accommodate the increased levels of uric acid. The identity of these "other" genes is unknown, and future research leading to their identification would be especially edifying. The fact that multiple independent mutations occurred in the uricase gene during hominoid evolution, with parallel mutations in some New World and Old World monkeys, is compatible with (although not proof of) the hypothesis that uricase inactivation provided some benefit.11Watanabe S. Kang D.H. Feng L. et al.Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity.Hypertension. 2002; 40: 355-360Crossref PubMed Scopus (482) Google ScholarAnother argument frequently invoked in support of this hypothesis is the ability of the human kidney to return a large proportion of the filtered urate to the circulation. It is tempting to assume that if uric acid was a metabolic waste product with no physiologic value, the kidney would not invest resources in the reabsorption of approximately 90% of the filtered urate. In fact, one of the great pioneers of renal physiology, the late Robert Berliner,12Giebisch G, Kennedy T. National Academy of Sciences Biographical Memoir: Robert W. Berliner, 1915-2002. Available at: http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/berliner-robert-w.pdf. Accessed August 1, 2012.Google Scholar specifically commented that it "makes no sense" for the human kidney to reclaim uric acid.13Gutman A.B. Renal excretion of uric acid in normal and gouty man.Arthritis Rheum. 1965; 8: 665-670Crossref PubMed Scopus (6) Google Scholar However, renal reabsorption of a substance does not invariably mean that the substance is needed for the whole organism, as can be exemplified by the case of urea, which is retained only to facilitate water conservation before its eventual fate of excretion. It is unlikely that renal handling of urate evolved according to this simple logic, and the intricate pathways for urate transport in the kidney may have evolved for other, more complex reasons (eg, to prevent crystal deposition and protect against kidney disease). If uric acid does indeed have biological functions that made elevated serum urate levels evolutionarily advantageous, what could these functions be? Several hypotheses can be formulated, combining scientific speculation with varying degrees of factual evidence. A comprehensive review of these hypotheses and of all the evidence for and against them is beyond the scope of this article, but a brief summary is provided in the following paragraphs. Uric acid has long been viewed as an inert metabolic product, with the sole mission (in humans and higher primates) of shuttling purine waste to the exterior world. This role is undoubtedly important, but could it have been, in itself, a determinant of evolutionary benefit? Organisms that excrete nitrogen primarily as uric acid (uricotelics), such as birds and some terrestrial reptiles, are excellent water conservers14Shoemaker V.H. Nagy K.A. Osmoregulation in amphibians and reptiles.Annu Rev Physiol. 1977; 39: 449-471Crossref PubMed Scopus (198) Google Scholar, 15Braun E.J. Integration of organ systems in avian osmoregulation.J Exp Zool. 1999; 283: 702-707Crossref Scopus (15) Google Scholar because they excrete some or all uric acid as crystals (the white color in bird droppings). In birds and reptiles, this is in part possible because the ureters empty directly into the cloaca, allowing further water reabsorption and uric acid precipitation without retention of calculi. Although urea remains the primary means of nitrogen excretion in hominoids, one could speculate that uricase inactivation, by increasing the proportion of nitrogen excreted as uric acid, may have rendered our ancestors more adept at conserving water (likely an important trait in the hot climate of Africa 30 million years ago). However, this scenario is extremely unlikely, because only uric acid excreted in solid form (not dissolved in the urine) is meaningful for water conservation. Humans and primates do not normally discharge large amounts of uric acid crystals in the urine, and even though there are 3 nitrogen molecules per urate molecule (as opposed to 2 for urea), the amount excreted per day is only a few millimoles, a small fraction of total nitrogen excretion. Another hypothesis related to the role of uric acid as metabolic waste is that uricase inactivation led to increased disposal of endogenously produced uric acid in the gut and possibly to changes in the intestinal microbiota, with a higher prevalence of bacteria capable of uricolysis. In turn, these bacteria could have had other advantageous effects on digestion, metabolism, or the immune system. This is highly speculative, not covered, to our knowledge, by previous publications in the field, but it is nevertheless plausible and merits further exploration. More than 30 years ago, Ames and colleagues16Ames B.N. Cathcart R. Schwiers E. Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis.Proc Natl Acad Sci U S A. 1981; 78: 6858-6862Crossref PubMed Scopus (2377) Google Scholar hypothesized that higher serum uric acid levels might have been beneficial during hominoid evolution because of the antioxidant properties of uric acid. Loss of l-gulonolactone oxidase, the enzyme responsible for ascorbic acid (vitamin C) synthesis, preceded the loss of uricase during primate evolution and may have raised the selection pressure for augmentation of an already existing alternative antioxidant system. Although the antioxidant capacity of uric acid is much smaller than that of vitamin C,17Frei B. England L. Ames B.N. Ascorbate is an outstanding antioxidant in human blood plasma.Proc Natl Acad Sci U S A. 1989; 86: 6377-6381Crossref PubMed Scopus (1737) Google Scholar uric acid could potentially compensate by its much higher concentration in the extracellular fluid compartment. In addition, uric acid is more effective than vitamin C at neutralizing peroxynitrite, an important oxidant produced from the reaction between nitric oxide and hydrogen peroxide.18Kuzkaya N. Weissmann N. Harrison D.G. Dikalov S. Interactions of peroxynitrite with uric acid in the presence of ascorbate and thiols: implications for uncoupling endothelial nitric oxide synthase.Biochem Pharmacol. 2005; 70: 343-354Crossref PubMed Scopus (186) Google Scholar Whether this was sufficient to confer an evolutionary advantage for uricase inactivation is not known. What is known, however, is that higher uric acid levels in the modern human are epidemiologically correlated with conditions that are, in turn, associated with increased oxidative stress, such as atherosclerosis, obesity, diabetes, and the metabolic syndrome.19Gagliardi A.C. Miname M.H. Santos R.D. Uric acid: a marker of increased cardiovascular risk.Atherosclerosis. 2009; 202: 11-17Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar This could be interpreted as an adaptive response, with more uric acid retained in the circulation in an attempt to offset disease-associated oxidative stress. However, it is equally compatible with the opposite conjecture that uric acid contributes to the pathogenesis of these conditions. Paradoxically, one of the ways in which uric acid has been proposed to contribute to disease is through its conditional pro-oxidant effect. Like most antioxidants, uric acid is in fact a redox agent, capable of both antioxidation and pro-oxidation.20Hayden M.R. Tyagi S.C. Uric acid: a new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: the urate redox shuttle.Nutr Metab (Lond). 2004; 1: 10Crossref PubMed Scopus (333) Google Scholar, 21Sautin Y.Y. Johnson R.J. Uric acid: the oxidant-antioxidant paradox.Nucleosides Nucleotides Nucleic Acids. 2008; 27: 608-619Crossref PubMed Scopus (575) Google Scholar The balance between the two is dictated by a very complex interplay of factors, including concentration of uric acid, the nature and concentration of free radicals, the presence and concentration of other antioxidant mechanisms, and others. It is becoming increasingly clear that uric acid may be antioxidant in certain conditions and pro-oxidant in others. It is important to note that among all theories related to uric acid, the antioxidant hypothesis is most often presented in the literature as established fact, although the value of uric acid as antioxidant in humans in vivo is far from proved.22Hershfield M.S. Roberts 2nd, L.J. Ganson N.J. et al.Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo.Proc Natl Acad Sci U S A. 2010; 107: 14351-14356Crossref PubMed Scopus (109) Google Scholar Johnson and colleagues proposed what is arguably the most intriguing theory for the role of uric acid in human evolution,11Watanabe S. Kang D.H. Feng L. et al.Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity.Hypertension. 2002; 40: 355-360Crossref PubMed Scopus (482) Google Scholar, 23Johnson R.J. Segal M.S. Srinivas T. et al.Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link?.J Am Soc Nephrol. 2005; 16: 1909-1919Crossref PubMed Scopus (245) Google Scholar based on the premise that sodium intake has been low for millions of years in our species' history. According to this theory, the antinatriuretic and vascular effects of elevated uric acid contributed to blood pressure maintenance during a time when climatic changes forced early hominoids to better conserve sodium. At the time, uricase inactivation was thus advantageous. The advent of increased salt availability and intake over the past 10,000 years, with the most dramatic increases in intake seen during the past century, transformed this system of sodium conservation into an essentially maladaptive trait postulated to contribute to the modern epidemic of hypertension. Whether loss of uricase function in the Miocene epoch was indeed related to blood pressure maintenance ("the good") remains speculative, but current evidence, albeit limited, is compatible with a role for uric acid in modern human hypertension ("the bad"). Available data include epidemiologic correlations between blood pressure and circulating uric acid and animal studies in which uric acid levels were manipulated experimentally to explore causality. It should be noted, however, that rodents have functional uricase and are ill equipped to handle hyperuricemia, making them less than adequate models for the study of any uric acid–related condition. The most compelling evidence to date for a causal role of uric acid in hypertension comes from one pilot trial of 30 adolescents (11-17 years) with newly diagnosed stage 1 primary hypertension and borderline hyperuricemia (≥360 μmol/L), who were treated with allopurinol and placebo (4 weeks each) in a randomized double-blinded crossover design.24Feig D.I. Soletsky B. Johnson R.J. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial.JAMA. 2008; 300: 924-932Crossref PubMed Scopus (773) Google Scholar Adolescents were selected for this study because the potential link between uric acid and hypertension is likely "cleaner" in this age group, whereas it may be plagued by multiple confounders in older individuals with longer standing hypertension and associated comorbidities. The fact that blood pressure was decreased by allopurinol in this trial provides an encouraging proof of principle. However, the study had a number of limitations (well detailed by the authors), and does not permit generalization in the absence of further research. It is well known that uric acid crystal deposition in gout causes inflammation, but this has long been considered a nonspecific effect. More recent evidence proposed that uric acid is released from injured somatic cells as monosodium urate (MSU) crystals and functions as an innate immunity enhancer or "danger signal," by stimulating the maturation of dendritic cells and augmenting the response of CD8+ T cells to an antigen codelivered with MSU in mice.25Shi Y. Evans J.E. Rock K.L. Molecular identification of a danger signal that alerts the immune system to dying cells.Nature. 2003; 425: 516-521Crossref PubMed Scopus (1411) Google Scholar These findings were specific for MSU crystals, and the effect was not seen when MSU crystals were replaced with other crystals with similar physical properties. Crystalline MSU, but not other crystals, has also been shown to activate the inflammasome, a multiprotein complex that participates in innate immunity and in the initiation of inflammation.26Martinon F. Petrilli V. Mayor A. Tardivel A. Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome.Nature. 2006; 440: 237-241Crossref PubMed Scopus (3953) Google Scholar Although these findings are extremely provocative, their importance for human biology has not been established, and whether MSU crystal–mediated effects on innate immunity and inflammation differ in species with or without functional uricase is unknown. One could speculate that uric acid, as an enhancer of innate immunity, is beneficial for the organism. It is also possible that some of the detrimental effects of hyperuricemia, beyond gout, are caused by elevated levels of MSU crystals and their effects on inflammatory and immune responses. Humans have adapted to circulating uric acid levels that are 5- to 20-fold higher than in most other mammals. The definition of hyperuricemia in adults is not universally agreed on, but commonly used thresholds are in the range of >6 to 7 mg/dL (>350-400 μM/L), usually higher for men than for women. Hyperuricemia thresholds are based either on the solubility limit of urate in the extracellular fluid compartment at physiologic pH (∼420 μM/L) or on distribution curves in normal individuals using classic 2 standard deviations above the mean; in some cases they are arbitrarily set based on relative risk of uric acid–associated disease. It is important to note, however, that although cutoffs are convenient for clinical practice, defining hyperuricemia (or sometimes "mild" hyperuricemia) based on precise values has no biological rationale, because one cannot treat a continuous variable such as uric acid as dichotomous. Urate levels rise to greater than commonly accepted thresholds in conditions of excessive purine intake, endogenous defects in purine metabolism, and/or inadequate uric acid excretion. In turn, persistent clinical hyperuricemia can cause gout and tophi and is associated with kidney stones. Beyond these classic clinical manifestations, and irrespective of their presence, various degrees of hyperuricemia have also been associated with hypertension (as discussed earlier), preeclampsia, obesity, the metabolic syndrome, and chronic kidney disease (including but not limited to chronic uric acid nephropathy). However, as always in biology, correlation should not be mistaken for causation. Evidence for causation in all these cases is relatively scarce and certainly inconclusive. One unifying element emerges from all the controversies surrounding the roles of uric acid in human biology: whether friend or foe, uric acid is likely much more than a waste product of purine metabolism. Uric acid homeostasis is tightly controlled, with the kidney assuming a pivotal role (Fig 1). Uric acid excretion rate is the product of the filtered load (which can be approximated as plasma ultrafilterable urate × glomerular filtration rate) and fractional excretion of urate (FEUA), which represents the percentage of filtered urate that is excreted in the final urine. FEUA can be estimated from the ratio of urate clearance (CUA) to creatinine clearance (CCr), calculated using plasma (P) and urinary (U) creatinine and urate values obtained from simultaneous spot urine and blood samples: FEUA = CUA/CCr × 100% = [(UUA × urine sample volume)/PUA]/[(UCr × urine sample volume)/PCr] ×100% = (UUA × PCr)/(PUA × UCr) × 100%. In adult humans, under normal conditions FEUA is approximately 10% (range 7%-12%) and is usually higher in women than in men. FEUA is higher in children, averaging 35% in newborns, 13% to 26% in children less than 1 year, and then decreases progressively to adult levels despite increasing urate filtered load.27Passwell J.H. Modan M. Brish M. Orda S. Boichis H. Fractional excretion of uric acid in infancy and childhood. Index of tubular maturation.Arch Dis Child. 1974; 49: 878-882Crossref PubMed Scopus (32) Google Scholar, 28Stapleton F.B. Linshaw M.A. Hassanein K. Gruskin A.B. Uric acid excretion in normal children.J Pediatr. 1978; 92: 911-914Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 28aStiburkova B. Bleyer A.J. Changes in serum urate and urate excretion with age.Adv Chronic Kidney Dis. 2012; 19Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar This fall in FEUA is indicative of maturational changes in renal urate transport, likely involving complex molecular mechanisms29Baum M. Quigley R. Satlin L. Maturational changes in renal tubular transport.Curr Opin Nephrol Hypertens. 2003; 12: 521-526Crossref PubMed Scopus (27) Google Scholar that are beyond the scope of this article. Further discussion of urate transport herein refers only to the adult kidney. As with most other biological processes, there are similarities and differences between the physiologic process of renal urate handling in humans, other mammals, and nonmammalian organisms. Teleologically, the differences can be attributed to 2 major factors: first, inactivation of uricase in humans and higher primates led to uric acid levels (and thus filtered loads) up to 2 orders of magnitude higher than in other mammals; second, although humans and other mammals primarily use urea as vehicle for nitrogen excretion (a mode of excretion termed ureotelism), other species such as birds and snakes use primarily uric acid (uricotelism), relying on a combination of high filtered load and FEUA >100% (net secretion). Consequently, there are wide variations in both filtered load and FEUA among vertebrates, with only higher primates being similar to humans in both respects. This is one of the most serious limitations fa
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