Uric Acid: A Clearer Focus

Abstract

Plasma phosphorus and uric acid/urate levels were removed from clinical laboratories' metabolic panels nearly 3 decades ago. There was insufficient evidence for their continued measurement. Moreover, fears of treating asymptomatic hyperuricemia with allopurinol, with its risk of side effects and hypersensitivity, contributed to uric acid's removal from the metabolic panel. Subsequently, the evidence base for both of these nephrocentric molecules developed. This issue of Advances in Chronic Kidney Disease converges on uric acid/urate, which gained preeminence in hominoids by virtue of the loss of the uricase gene during evolution through the Miocene Epoch.The guest editors, Drs. Anthony J. Bleyer and Stanislav Kmoch have, like a large reflecting telescope, collected an impressive amount of information from their respective contributors and concentrated it, producing a much clearer image of this purine-derived metabolic end-product’s role in human physiology and pathophysiology. Their enhanced picture clarifies our knowledge regarding normal uric acid/urate physiology and pathophysiology (Fig 1). Greater insight is provided not only for gout and uric acid stone formation but also for hypertension and CKD, as they relate to genetic tubulointerstitial disorders, including hyperuricemic mutations of the UMOD (uromodulin),1Hodanova K. Majewski J. Kublova M. et al.Mapping of a new candidate locus for uromodulin-associated kidney disease (UAKD) to chromosome 1q41.Kidney Int. 2005; 68: 1472-1482Crossref PubMed Scopus (29) Google Scholar REN (renin),2Zivna M. Hulkova H. Matigon M. et al.Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure.Am J Hum Genet. 2009; 85: 204-213Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 3Bleyer A.J. Zivna M. Hulkova H. et al.Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone.Clin Nephrol. 2010; 74: 411-422Crossref PubMed Google Scholar and HNF-1b (hepatocyte nuclear factor-1 beta) genes.4Bingham C. Ellard S. van't Hoff W.G. et al.Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1beta gene mutation.Kidney Int. 2003; 63: 1645-1651Crossref PubMed Scopus (131) Google ScholarOnce a highbrow disease of the genteel, gout has seen a resurgence in the past 2 decades in the United States. The consequence of hyperuricemia, gout, and uric acid nephrolithiasis may result from perturbations of renal handling of uric acid. Although approximately 90% of the ultrafiltered uric acid undergoes reabsorption, the kidneys excrete only about 60% to 70% of the body's uric acid; the rest is secreted by the bowel. Recent investigations have overturned the previously held conception of renal urate handling. This end-product of purine metabolism is filtered, reabsorbed, and secreted by specific proximal tubule organic anion transporters, such as URAT1 (uric acid transporter-1 protein)5Enomoto A. Kimura H. Chairoungdua A. et al.Molecular identification of a renal urate anion exchanger that regulates blood urate levels.Nature. 2002; 417: 447-452Crossref PubMed Scopus (1129) Google Scholar and GLUT9a (glucose transporter-like protein 9a), now referred to simply as GLUT9.6Augustin R. Carayannopoulos M.O. Dowd L.O. Phay J.E. Moley J.F. Moley K.H. Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking.J Biol Chem. 2004; 279: 16229-16236Crossref PubMed Scopus (222) Google Scholar It is now clear that urate is not reabsorbed and secreted, contradicting the classic model of presecretory reabsorption, secretion, and postsecretory reabsorption. Also, it is now appreciated that the uricosuric agents losartan, furosemide, probenecid, and benzbromarone inhibit apical URAT1, whereas pyrazinamide stimulates this transporter. On the basolateral aspect, GLUT9 is inhibited by losartan, probenecid, and benzbromarone, thereby inducing uricosuria.5Enomoto A. Kimura H. Chairoungdua A. et al.Molecular identification of a renal urate anion exchanger that regulates blood urate levels.Nature. 2002; 417: 447-452Crossref PubMed Scopus (1129) Google ScholarThe incidence and prevalence of gout and uric acid stones have risen concomitantly with the ongoing epidemic of obesity, metabolic syndrome, and type 2 diabetes. The culprit for gout is likely endogenous uric acid overproduction fueled by the exogenously introduced high fructose corn syrup—the standard American dietary sweetener—which upon cellular metabolism induces adenine release and subsequent uric acid production. This effect is mediated by the urate transporter SLC2A9 that encodes GLUT9 and is inhibited by fructose.7Vitart V. Rudan I. Hayward C. et al.SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.Nat Genet. 2008; 40: 437-442Crossref PubMed Scopus (581) Google Scholar A spike in serum urate concentrations follows ingestion of high-fructose corn syrup–containing soft drinks.8Le M.T. Frye R.F. Rivard C.J. et al.Effects of high-fructose corn syrup and sucrose on the pharmacokinetics of fructose and acute metabolic and hemodynamic responses in healthy subjects.Metabolism. 2012; 61: 641-651Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Without a reduction in the use of this sweetener, the incidence of gout will likely increase, even with adoption of the oft-prescribed, classic “low uric acid” diet and the recently described “urate-lowering drinks,” coffee and milk, the latter of which contains the uricosuric orotic acid.9Okonkwo P.O. Kinsella J.E. Orotic acid in food milk powders.Am J Clin Nutr. 1969; 22: 532-534PubMed Google Scholar Conversely, uric acid stones are more the result of an “unduly acidic urine pH” associated with obesity, metabolic syndrome, and insulin resistance.Hopefully, a “low uric acid diet,” which also reduces net acid production, and consumption of more fruits and vegetables will be accompanied by a reduction in the frequency of uric acid stone formation. In addition, with advancing knowledge of renal urate handling, opportunities for the specific augmentation of uric acid excretion by the kidneys may arise in the pharmacologic literature, although urinary alkalinization will be necessary to ensure uric acid's continued solubility. Until then, we depend on a mainstay of xanthine oxidase inhibition by the purine analogue, allopurinol (Ki 0.5 μM),10Miyamoto Y. Akaike T. Yoshida M. Goto S. Horie H. Maeda H. Potentiation of nitric oxide-mediated vasorelaxation by xanthine oxidase inhibitors.Proc Soc Exp Biol Med. 1996; 211: 366-373Crossref PubMed Scopus (75) Google Scholar or the more potent, nonpurine inhibitor, febuxostat (Ki 0.6 nM), which is metabolized in the liver.11Takano Y. Hase-Aoki K. Horiuchi H. et al.Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase.Life Sci. 2005; 76: 1835-1847Crossref PubMed Scopus (264) Google Scholar The former's association with hypersensitivity reactions has often given pause to its prescription; however, these reactions may result from genetic predisposition rather than dose accumulation.Uric acid's role in producing a reversible form of high blood pressure stems from increasing levels of uric acid that may induce the renin-angiotensin system, which, if prolonged, becomes resistant to the uric acid–lowering effect of xanthine oxidase inhibitors.12Mazzali M. Hughes J. Kim Y.G. et al.Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism.Hypertension. 2001; 38: 1101-1106Crossref PubMed Scopus (1014) Google Scholar, 13Mazzali M. Kanellis J. Han L. et al.Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure independent mechanism.Am J Physiol Renal Physiol. 2002; 282: F991-F997PubMed Google Scholar Structural damage from persistent, sodium-dependent hypertension transcends an initial uric acid–mediated vasoconstriction, induced by restriction of vasodilatory nitric oxide, coincident with afferent arteriolopathy, a pathologic condition not unsurprisingly magnified by concurrent cyclosporine administration.This mechanism of hypertension has been demonstrated by pharmacologically induced hyperuricemic hypertension in a rodent model, and correlative studies that have repeatedly illustrated an epidemiologic association between uric acid and elevated systolic and diastolic blood pressures.14Feig D.I. Johnson R.J. Hyperuricemia in childhood primary hypertension.Hypertension. 2003; 42: 247-252Crossref PubMed Scopus (401) Google Scholar This association is strongest in adolescents in whom treatment of hypertension with allopurinol restored blood pressure to normal.15Feig 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 (732) Google Scholar Moreover, a non-uric acid-mediated reduction of the blood pressure by allopurinol has been detected in an experimental rat model of hypertension, and this effect may involve CD-5 cells as well as the renin-angiotensin system.Would lowering the uric acid in patients with CKD provide an improved outcome? The data regarding this hypothesis are sparse but compelling. First, however, one must acknowledge that although hyperuricemia is worsened by progressive CKD, its serum concentration should have been higher than measured at any given level of CKD. Whether there is enhanced gut secretion of uric acid and uricolysis16Sorensen L.B. Levinson D.J. Origin and extrarenal elimination of uric acid in man.Nephron. 1975; 14: 7-20Crossref PubMed Scopus (98) Google Scholar and/or downregulation of xanthine oxidase activity in urate-producing tissues is conjectural but plausible. In addition, the hyperuricemia of CKD may be protective, since uric acid/urate may act as an antioxidant in some circumstances, scavenging reactive oxygen species (Fig 1).17Hayden 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 (316) Google Scholar, 18Sautin Y.Y. Johnson R.J. Uric acid: the oxidant-antioxidant paradox.Nucleosides Nucleotides Nucleic Acids. 2008; 27: 608-619Crossref PubMed Scopus (508) Google Scholar, 19Baillie J.K. Bates M.G. Thompson A.A. et al.Endogenous urate production augments plasma antioxidant capacity in healthy lowland subjects exposed to high altitude.Chest. 2007; 131: 1473-1478Crossref PubMed Scopus (55) Google Scholar In short, the hyperuricemia of CKD deserves some equanimity, as it may confer some biologically and clinically positive aspects.20Siu Y.P. Leung K.T. Tong M.K. Kwan T.H. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.Am J Kidney Dis. 2006; 47: 51-59Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar, 21Goicoechea M. de Vinuesa S.G. Verdalles U. et al.Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.Clin J Am Soc Nephrol. 2010; 5: 1388-1393Crossref PubMed Scopus (640) Google ScholarMultiple cross-sectional studies have correlated elevated uric acid levels with reduced estimated glomerular filtration rate (GFR) and/or microalbuminuria. In a 54-person 1-year randomized interventional study of individuals with hyperuricemia and CKD stages 3 and 4, xanthine oxidase inhibition by allopurinol was salutary.20Siu Y.P. Leung K.T. Tong M.K. Kwan T.H. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.Am J Kidney Dis. 2006; 47: 51-59Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar Namely, progression of CKD was attenuated in those in the treatment group whose serum uric acid levels were purposefully diminished. A 2-year study that compared allopurinol to conventional therapy in 113 patients with estimated GFR less than 60 mL/min/1.73 m2 demonstrated a positive effect of allopurinol, whereby the treatment group had a lesser slope of decline of GFR.21Goicoechea M. de Vinuesa S.G. Verdalles U. et al.Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.Clin J Am Soc Nephrol. 2010; 5: 1388-1393Crossref PubMed Scopus (640) Google Scholar In fact, the slope of the treatment group was unchanged. Notably, because there is an increment of the serum uric acid concentration concomitant with a reduction in GFR, the relationship may be self-fulfilling. Obviously, larger interventional rather than observational trials of uric acid lowering are required.Forerunner reflector telescopes suffered from chromatic aberration as did our previous understanding of uric acid. Certainly, the authors of this issue of Advances in Chronic Kidney Disease have eliminated many of the distortions regarding this diprotic acid (Fig 2). Its refocusing into a much clearer image mandates its belated return to the metabolic panel and warrants its further investigation.Figure 2The nephrologist focuses sharply on the constellations of uric acid/urate, in order to resolve this entity's physiology and pathophysiology. Illustration by Tom Mattix, Mattix Illustration.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Plasma phosphorus and uric acid/urate levels were removed from clinical laboratories' metabolic panels nearly 3 decades ago. There was insufficient evidence for their continued measurement. Moreover, fears of treating asymptomatic hyperuricemia with allopurinol, with its risk of side effects and hypersensitivity, contributed to uric acid's removal from the metabolic panel. Subsequently, the evidence base for both of these nephrocentric molecules developed. This issue of Advances in Chronic Kidney Disease converges on uric acid/urate, which gained preeminence in hominoids by virtue of the loss of the uricase gene during evolution through the Miocene Epoch. The guest editors, Drs. Anthony J. Bleyer and Stanislav Kmoch have, like a large reflecting telescope, collected an impressive amount of information from their respective contributors and concentrated it, producing a much clearer image of this purine-derived metabolic end-product’s role in human physiology and pathophysiology. Their enhanced picture clarifies our knowledge regarding normal uric acid/urate physiology and pathophysiology (Fig 1). Greater insight is provided not only for gout and uric acid stone formation but also for hypertension and CKD, as they relate to genetic tubulointerstitial disorders, including hyperuricemic mutations of the UMOD (uromodulin),1Hodanova K. Majewski J. Kublova M. et al.Mapping of a new candidate locus for uromodulin-associated kidney disease (UAKD) to chromosome 1q41.Kidney Int. 2005; 68: 1472-1482Crossref PubMed Scopus (29) Google Scholar REN (renin),2Zivna M. Hulkova H. Matigon M. et al.Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure.Am J Hum Genet. 2009; 85: 204-213Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 3Bleyer A.J. Zivna M. Hulkova H. et al.Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone.Clin Nephrol. 2010; 74: 411-422Crossref PubMed Google Scholar and HNF-1b (hepatocyte nuclear factor-1 beta) genes.4Bingham C. Ellard S. van't Hoff W.G. et al.Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1beta gene mutation.Kidney Int. 2003; 63: 1645-1651Crossref PubMed Scopus (131) Google Scholar Once a highbrow disease of the genteel, gout has seen a resurgence in the past 2 decades in the United States. The consequence of hyperuricemia, gout, and uric acid nephrolithiasis may result from perturbations of renal handling of uric acid. Although approximately 90% of the ultrafiltered uric acid undergoes reabsorption, the kidneys excrete only about 60% to 70% of the body's uric acid; the rest is secreted by the bowel. Recent investigations have overturned the previously held conception of renal urate handling. This end-product of purine metabolism is filtered, reabsorbed, and secreted by specific proximal tubule organic anion transporters, such as URAT1 (uric acid transporter-1 protein)5Enomoto A. Kimura H. Chairoungdua A. et al.Molecular identification of a renal urate anion exchanger that regulates blood urate levels.Nature. 2002; 417: 447-452Crossref PubMed Scopus (1129) Google Scholar and GLUT9a (glucose transporter-like protein 9a), now referred to simply as GLUT9.6Augustin R. Carayannopoulos M.O. Dowd L.O. Phay J.E. Moley J.F. Moley K.H. Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking.J Biol Chem. 2004; 279: 16229-16236Crossref PubMed Scopus (222) Google Scholar It is now clear that urate is not reabsorbed and secreted, contradicting the classic model of presecretory reabsorption, secretion, and postsecretory reabsorption. Also, it is now appreciated that the uricosuric agents losartan, furosemide, probenecid, and benzbromarone inhibit apical URAT1, whereas pyrazinamide stimulates this transporter. On the basolateral aspect, GLUT9 is inhibited by losartan, probenecid, and benzbromarone, thereby inducing uricosuria.5Enomoto A. Kimura H. Chairoungdua A. et al.Molecular identification of a renal urate anion exchanger that regulates blood urate levels.Nature. 2002; 417: 447-452Crossref PubMed Scopus (1129) Google Scholar The incidence and prevalence of gout and uric acid stones have risen concomitantly with the ongoing epidemic of obesity, metabolic syndrome, and type 2 diabetes. The culprit for gout is likely endogenous uric acid overproduction fueled by the exogenously introduced high fructose corn syrup—the standard American dietary sweetener—which upon cellular metabolism induces adenine release and subsequent uric acid production. This effect is mediated by the urate transporter SLC2A9 that encodes GLUT9 and is inhibited by fructose.7Vitart V. Rudan I. Hayward C. et al.SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.Nat Genet. 2008; 40: 437-442Crossref PubMed Scopus (581) Google Scholar A spike in serum urate concentrations follows ingestion of high-fructose corn syrup–containing soft drinks.8Le M.T. Frye R.F. Rivard C.J. et al.Effects of high-fructose corn syrup and sucrose on the pharmacokinetics of fructose and acute metabolic and hemodynamic responses in healthy subjects.Metabolism. 2012; 61: 641-651Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Without a reduction in the use of this sweetener, the incidence of gout will likely increase, even with adoption of the oft-prescribed, classic “low uric acid” diet and the recently described “urate-lowering drinks,” coffee and milk, the latter of which contains the uricosuric orotic acid.9Okonkwo P.O. Kinsella J.E. Orotic acid in food milk powders.Am J Clin Nutr. 1969; 22: 532-534PubMed Google Scholar Conversely, uric acid stones are more the result of an “unduly acidic urine pH” associated with obesity, metabolic syndrome, and insulin resistance. Hopefully, a “low uric acid diet,” which also reduces net acid production, and consumption of more fruits and vegetables will be accompanied by a reduction in the frequency of uric acid stone formation. In addition, with advancing knowledge of renal urate handling, opportunities for the specific augmentation of uric acid excretion by the kidneys may arise in the pharmacologic literature, although urinary alkalinization will be necessary to ensure uric acid's continued solubility. Until then, we depend on a mainstay of xanthine oxidase inhibition by the purine analogue, allopurinol (Ki 0.5 μM),10Miyamoto Y. Akaike T. Yoshida M. Goto S. Horie H. Maeda H. Potentiation of nitric oxide-mediated vasorelaxation by xanthine oxidase inhibitors.Proc Soc Exp Biol Med. 1996; 211: 366-373Crossref PubMed Scopus (75) Google Scholar or the more potent, nonpurine inhibitor, febuxostat (Ki 0.6 nM), which is metabolized in the liver.11Takano Y. Hase-Aoki K. Horiuchi H. et al.Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase.Life Sci. 2005; 76: 1835-1847Crossref PubMed Scopus (264) Google Scholar The former's association with hypersensitivity reactions has often given pause to its prescription; however, these reactions may result from genetic predisposition rather than dose accumulation. Uric acid's role in producing a reversible form of high blood pressure stems from increasing levels of uric acid that may induce the renin-angiotensin system, which, if prolonged, becomes resistant to the uric acid–lowering effect of xanthine oxidase inhibitors.12Mazzali M. Hughes J. Kim Y.G. et al.Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism.Hypertension. 2001; 38: 1101-1106Crossref PubMed Scopus (1014) Google Scholar, 13Mazzali M. Kanellis J. Han L. et al.Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure independent mechanism.Am J Physiol Renal Physiol. 2002; 282: F991-F997PubMed Google Scholar Structural damage from persistent, sodium-dependent hypertension transcends an initial uric acid–mediated vasoconstriction, induced by restriction of vasodilatory nitric oxide, coincident with afferent arteriolopathy, a pathologic condition not unsurprisingly magnified by concurrent cyclosporine administration. This mechanism of hypertension has been demonstrated by pharmacologically induced hyperuricemic hypertension in a rodent model, and correlative studies that have repeatedly illustrated an epidemiologic association between uric acid and elevated systolic and diastolic blood pressures.14Feig D.I. Johnson R.J. Hyperuricemia in childhood primary hypertension.Hypertension. 2003; 42: 247-252Crossref PubMed Scopus (401) Google Scholar This association is strongest in adolescents in whom treatment of hypertension with allopurinol restored blood pressure to normal.15Feig 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 (732) Google Scholar Moreover, a non-uric acid-mediated reduction of the blood pressure by allopurinol has been detected in an experimental rat model of hypertension, and this effect may involve CD-5 cells as well as the renin-angiotensin system. Would lowering the uric acid in patients with CKD provide an improved outcome? The data regarding this hypothesis are sparse but compelling. First, however, one must acknowledge that although hyperuricemia is worsened by progressive CKD, its serum concentration should have been higher than measured at any given level of CKD. Whether there is enhanced gut secretion of uric acid and uricolysis16Sorensen L.B. Levinson D.J. Origin and extrarenal elimination of uric acid in man.Nephron. 1975; 14: 7-20Crossref PubMed Scopus (98) Google Scholar and/or downregulation of xanthine oxidase activity in urate-producing tissues is conjectural but plausible. In addition, the hyperuricemia of CKD may be protective, since uric acid/urate may act as an antioxidant in some circumstances, scavenging reactive oxygen species (Fig 1).17Hayden 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 (316) Google Scholar, 18Sautin Y.Y. Johnson R.J. Uric acid: the oxidant-antioxidant paradox.Nucleosides Nucleotides Nucleic Acids. 2008; 27: 608-619Crossref PubMed Scopus (508) Google Scholar, 19Baillie J.K. Bates M.G. Thompson A.A. et al.Endogenous urate production augments plasma antioxidant capacity in healthy lowland subjects exposed to high altitude.Chest. 2007; 131: 1473-1478Crossref PubMed Scopus (55) Google Scholar In short, the hyperuricemia of CKD deserves some equanimity, as it may confer some biologically and clinically positive aspects.20Siu Y.P. Leung K.T. Tong M.K. Kwan T.H. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.Am J Kidney Dis. 2006; 47: 51-59Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar, 21Goicoechea M. de Vinuesa S.G. Verdalles U. et al.Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.Clin J Am Soc Nephrol. 2010; 5: 1388-1393Crossref PubMed Scopus (640) Google Scholar Multiple cross-sectional studies have correlated elevated uric acid levels with reduced estimated glomerular filtration rate (GFR) and/or microalbuminuria. In a 54-person 1-year randomized interventional study of individuals with hyperuricemia and CKD stages 3 and 4, xanthine oxidase inhibition by allopurinol was salutary.20Siu Y.P. Leung K.T. Tong M.K. Kwan T.H. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.Am J Kidney Dis. 2006; 47: 51-59Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar Namely, progression of CKD was attenuated in those in the treatment group whose serum uric acid levels were purposefully diminished. A 2-year study that compared allopurinol to conventional therapy in 113 patients with estimated GFR less than 60 mL/min/1.73 m2 demonstrated a positive effect of allopurinol, whereby the treatment group had a lesser slope of decline of GFR.21Goicoechea M. de Vinuesa S.G. Verdalles U. et al.Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.Clin J Am Soc Nephrol. 2010; 5: 1388-1393Crossref PubMed Scopus (640) Google Scholar In fact, the slope of the treatment group was unchanged. Notably, because there is an increment of the serum uric acid concentration concomitant with a reduction in GFR, the relationship may be self-fulfilling. Obviously, larger interventional rather than observational trials of uric acid lowering are required. Forerunner reflector telescopes suffered from chromatic aberration as did our previous understanding of uric acid. Certainly, the authors of this issue of Advances in Chronic Kidney Disease have eliminated many of the distortions regarding this diprotic acid (Fig 2). Its refocusing into a much clearer image mandates its belated return to the metabolic panel and warrants its further investigation. The author expresses his gratitude to Michael J. Choi and David S. Goldfarb for their insightful comments during the generation of this editorial and to Pablo Buitrón de la Vega for his illustration depicting uric acid/urate pathophysiology.