Hypouricemia and tubular transport of uric acid

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Caldés Ruisánchez, ROBERTO MARCÉN LETOSA, R. Marcén Letosa, YESIKA AMEZQUITA ORJUELA, Y. Amezquita Orjuela, MILAGROS FERNÀNDEZ LUCAS, M. Fernández Lucas, MAITE RIVERA GORRIN, M. Rivera Gorrin, CRISTINA GALEANO ALVAREZ, C. Galeano Álvarez, ANA FERNÁNDEZ RODRÍGUEZ, A. Fernández Rodríguez, JOSE LUIS TERUEL BRIONES, J.L. Teruel Briones, CARLOS QUEREDA RODRÍGUEZ-NAVARRO, C. Quereda Rodríguez" "autores" => array:19 [ 0 => null 1 => array:2 [ "nombre" => "SILVIA" "apellidos" => "CALDÉS RUISÁNCHEZ" ] 2 => array:2 [ "Iniciales" => "S." "apellidos" => "Caldés Ruisánchez" ] 3 => array:2 [ "nombre" => "ROBERTO" "apellidos" => "MARCÉN LETOSA" ] 4 => array:2 [ "Iniciales" => "R." "apellidos" => "Marcén Letosa" ] 5 => array:2 [ "nombre" => "YESIKA" "apellidos" => "AMEZQUITA ORJUELA" ] 6 => array:2 [ "Iniciales" => "Y." "apellidos" => "Amezquita Orjuela" ] 7 => array:2 [ "nombre" => "MILAGROS" "apellidos" => "FERNÀNDEZ LUCAS" ] 8 => array:2 [ "Iniciales" => "M." 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Esparza Martín, V. García Nieto" "autores" => array:3 [ 0 => null 1 => array:4 [ "Iniciales" => "N." "apellidos" => "Esparza Martín" "email" => array:1 [ 0 => "noemiesparza@telefonica.net" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] ] ] 2 => array:3 [ "Iniciales" => "V." 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However, it is a biochemical finding that deserves attention since it may be associated with primary or secondary tubulopathies and other underlying conditions. Traditionally, hypouricemia has not been given the same importance as hyperuricemia, perhaps because of its lower incidence rate. However, hypouricemia is now increasingly common in nephrology consultations, as a greater number of patients with diabetic nephropathy are seen, and because it is increasingly common to see patients from different races and countries. Moreover, from a physiological standpoint, there have been new contributions on the mechanisms of uric acid transport in the renal proximal tubule. Therefore, new therapies to block or stimulate these transport mechanisms may become available in the coming years. NORMAL uric acid Plasma values and urinary excretion Serum urate concentrations are higher in men than in women. Thus, hyperuricemia is defined as the existence of values above 7mg/dl in men and higher than 6mg/dl in women. Urate excreted in the urine accounts for approximately 70% of that produced daily, with the rest excreted in the faeces. Normal uricosuria values in adults are 620±75mg/day.1,2 Urate elimination is best studied as an excretion index (normal: 0.40±0.09mg/100ml)3 or preferably as fractional excretion (normal: 7.25±2.98%).4,5 PHYSIOLOGICAL AND HISTORICAL BACKGROUND OF RENAL TUBULAR HANDLING OF URIC ACID. NEW DEVELOPMENTS In the early twentieth century, it was assumed that uric acid was filtered by the kidney, and thus excreted in the urine. However, in 1950, Berliner et al. tried to find an explanation for the finding that uric acid clearance was lower than that of creatinine. To explain this “incomprehensible phenomenon”, the authors induced hyperuricemia in a group of healthy subjects by an overload of lithium carbonate. Studying the clearances of inulin and urate, they came to the conclusion that “urate is excreted by glomerular filtration and active tubular reabsorption”.6 That same year, Praetorius and Kirk described the case of a patient with a severe hypouricemia in which the clearance of uric acid was higher than creatinine. This led them to assume that this individual’s kidney secreted uric acid. It was the first reported case of renal tubular hypouricemia.7 The existence of a tubular secretion phase for uric acid was again proposed in 1957 when Gutman and Yu studied 300 patients with gout and concluded that a reduction in the tubular secretion of uric acid could explain the reduction of uricosuria found.8 Four years later, those same authors published their 3-component theory. Uric acid circulating in the blood is passively filtered at the glomerulus. It is later actively reabsorbed in the proximal tubule and then secreted into the tubular lumen.9 In the early 70s, Diamond and Paolino, through the sequential combination of various uricosuric medications (sulphinpyrazone, probenecid and salicylates at high doses) and pyrazinamide in healthy subjects, reported the existence of a reabsorption of urate in an area distal to secretion (postsecretory reabsorption).10 The 3-component hypothesis had thus become 4. The proportion of filtered urate reabsorbed in the proximal tubule was 99%-100%, leaving 0%-2% of filtered urate in the tubular lumen. Subsequently, a tubular secretory phase is produced, with 50% of the urate initially filtered remaining in the tubular lumen. Finally, this leads to proximal tubular reabsorption, quantified at 80% of that secreted. This explains how the amount of uric acid excreted in the urine is approximately 10% of the amount of urate filtered (Figure 1). Thus, defects in the tubular handling of uric acid associated with hypouricemia could be caused by isolated or combined defects in the presecretory and/or postsecretory reabsorption, or by an increase in tubular secretion. To establish the causal mechanism, pharmacological tests were used with pyrazinamide stimulus (to inhibit tubular secretion) and probenecid or benzbromarone (to inhibit postsecretory tubular reabsorption).11 Currently, these tests are not usually performed in daily practice. Knowledge of the metabolism of uric acid did not change until the arrival of new developments resulting from the application of molecular biology techniques. These identified several transporters and proteins that have demonstrated the complexity of urate ion handling in the proximal tubule12 (Figure 2). The URAT1 transporter that reabsorbs the filtered urate was identified by Enomoto et al. in 2002.13 It is located in the apical membrane of proximal tubule cells and is encoded by the gene SLC22A12(URAT1), which belongs to the organic anion transporter (OAT) family.14 In the human kidney, urate is transported via URAT1 through the apical membrane of the proximal tubular cells, in exchange for anions transported towards the tubular lumen to maintain the appropriate electrical balance (Figure 2). Mutations in the SLC22A12 gene encoding URAT1 have been described in Japanese patients suffering from renal tubular hypouricemia.15-17 Mutations in this gene have also been described in Korean patients18 and in 3 Israeli families of Iraqi origin.19 These patients all have very low levels and high fractional excretion of uric acid (approx. 40%-90%) and a low uricosuric response to probenecid and pyrazinamide.15 Both losartan and benzbromarone exert their uricosuric action by inhibiting URAT1.20 Uric acid enters the peritubular space due to basolateral transporters. In 2003, Jutabna et al. identified a new voltage sensitive organic ion transporter, the URATv1 (OATv1), which facilitates the exit of urate from the cell,21 and which is encoded by the gene SLC2A9.22 It was later called GLUT9 as it was known to belong to a family of proteins facilitating the transport of hexoses (fructose, glucose).23 Two variants of the protein have been described: a GLUT9L isoform which is expressed primarily in the basolateral membrane of the proximal tubule cells, and a GLUT9S isoform which is expressed exclusively in the apical membrane of these cells.24 For patients with the latter renal tubular hypouricemia, the urate reabsorption reduction occurs on both sides of the renal proximal tubule cells25,26 (Figure 2). In these patients, fractional excretion of urate exceeds 150%.26 The heterozygous carriers have moderately reduced urate levels.26 GLUT9 is considered the main regulator of urate levels in humans.27 Thus, it has been reported that different polymorphisms in the SLC2A9 gene influence the levels of urate over a wide range of values.28-30 Therefore, in the future this may be a therapeutic target in patients with gout and related cardiovascular diseases.25 Also, the association between certain polymorphisms of the SLC2A9 gene and the development of nephrolithiasis has been described.31 However, the question of renal handling of uric acid is still a complex one. In 1985, Guggino and Aronson suggested that pyrazinamide stimulated the tubular reabsorption of urate by a Na+-dependent cotransporter.32 In other words, contrary to previously thought, they proposed that it inhibited tubular secretion. During the following years, it was confirmed that there was a link between acid and sodium reabsorption in the proximal tubule.33 In 2004, a molecular candidate was described for this type of cotransport, SLC5A8, a Na+-monocarboxylate transporter that would carry out a Na+-dependent cotransport of the monocarboxylic anions lactate, butyrate, nicotinate, beta-hydroxybutyrate and acetoacetate.34,35 Interestingly, the human gene SLC5A8 has been reported as a tumour suppressor, whose silencing may contribute to carcinogenesis and the progression of various tumours. However, as shown in Figure 2, SLC5A8 acts synergistically with URAT1. This link between the apical tubular reabsorption of urate and the reabsorption of Na+ would explain hyperuricemia induced by ketoacids in diabetic ketoacidosis,36 ethanol intoxication,37 treatment with pyrazinamide38 and the metabolic syndrome.39 It is worth remembering that hyperinsulinemia is known to increase reabsorption of Na+.40 An increase in serum concentrations of these anions, once filtered, would increase their reabsorption in the proximal tubule which, in turn, would enhance the reabsorption of urate by promoting the activity of URAT and the exchange of these anions with filtered urate.41 Finally, excretion by the kidney of a variety of drugs and metabolites which are dicarboxylic organic anions is mediated, via exchange with urate, by a family of multispecific OAT organic anion transporters (OAT genes), which are part of the SLC22 solute transporter family. Different OATs are located in both the apical (OAT2, OAT4) and the basolateral (OAT1 and OAT3) membranes of the renal proximal tubules.42 It has been suggested that the uricosuric effect of probenecid is due to its inhibition of OAT4.12 Therefore, acceptance of the 4-components model (Figure 1) requires an anatomical separation of presecretory reabsorption, tubular secretion and postsecretory reabsorption. At present, in the absence of detailed physiological characterisation and intrarenal location of the various human transporters listed above, the maintenance of this scheme cannot be sustained. HYPOURICEMIA Hypouricemia is diagnosed when plasma levels of uric acid are less than or equal to 2.0mg/dl.43 However, Sperling proposed 2.1mg/dl to be used as the normal lower limit for women and 2.5mg/dl in men.44 It is reported to occur in 0.8% of hospitalised patients and 0.2% of the general population.45 An article was published in 1969 from work carried out in hospitals in Toronto (Canada) which examined the clinical usefulness of 1,000 uric acid determinations. These were not requested by the physicians responsible for the patients, but the biochemists included them in the analytical results.46 Serum uric acid levels below 2.6mg/dl were found in 44 patients (4.4% of the sample). Clinical hypouricemia was questioned in only one case, and considered irrelevant in the 43 remaining cases. The diagnoses of these 44 patients were mixed and none was diagnosed with the classic causes of hypouricemia, such as Fanconi syndrome47 or Wilson's disease. The differential diagnosis of hypouricemia is made based on the fractional excretion of uric acid (Table 1). Hypouricemia with a reduced fractional excretion of uric acid is associated with xanthinuria, treatment with allopurinol, neoplasms and hepatic function abnormalities.48 Rasburicase treatment also produces hypouricemia with reduced fractional excretion of uric acid, as it is a urolithic agent that catalyses the enzymatic oxidation of uric acid into allantoin, a water soluble product easily excreted by the kidneys. From a nephrological point of view, it is worth highlighting the hypouricemia associated with hereditary xanthinuria (autosomal recessive deficiency of the xanthine oxidase enzyme), as it is a severe hypouricemia of less than 1mg/dl associated with a decreased uric acid fractional excretion and increased xanthine excretion. The confirmation of the diagnosis is made by liver or intestinal biopsy which shows the reduced enzymatic activity. Hypouricemia with a high fractional excretion of uric acid is mainly caused by renal tubular hypouricemia, either in an isolated15-19,25,26 or complex tubulopathy, such as Toni-Debré-Fanconi syndrome, caused by various conditions such as cystinosis, Lowe syndrome or heavy metal poisoning. Other causes are the use of salicylates, intravenous contrast media, total parenteral nutrition, Hodgkin's disease and other neoplasias, Wilson's disease and other causes of cirrhosis, diabetes mellitus and syndrome of inappropriate secretion of ADH. Finally, an association has been described with hyperparathyroidism,49 thiazide-induced hyponatremia50 and hyperbilirubinemia51 (Table 1). It must also be remembered that oestrogens, losartan, dicumarol, salicylates at high-dose and trimethoprim-sulphamethoxazole are drugs that increase uric acid excretion. Also, from a nephrological point of view, the existence of hypouricemia in diabetes mellitus, hypouricemia associated with hyponatremia and hypouricemia secondary to tubulopathies should be noted. It has been reported that patients with diabetes mellitus may have hypouricemia.56,57 This is observable in both type 1, insulin-dependent diabetes mellitus patients58 and in type 2, non-insulin-dependent patients.59,60 This implies that the pathophysiology must initially be connected with something common to both conditions. The reduction in plasma uric acid is due to an increase in its renal clearance58,61-63 and it is only observed in patients with normal GFR levels. When uricosuric stimulus tests were performed, a defect in presecretory reabsorption,68 postsecretory62 or a combination of both 62,64 were seen. In some studies, increased uricosuria has been attributed to glomerular hyperfiltration,59,60 therefore, hypouricemia could be a marker for the onset of diabetic kidney disease.60 In general, though not always, a positive relationship has been described between glycosuria and uricosuria, therefore, there would be interference between the tubular reabsorption of glucose and the tubular capacity to reabsorb urate.61 Hypouricemia would therefore be likely in the case of poor control of the disease. Thus, the hypouricemia would be associated with poor disease control, hyperfiltration or a late onset of nephropathy.69 Regarding the value of hypouricemia in the presence of hyponatremia, hypouricemia secondary to extracellular volume expansion is associated with decreased proximal reabsorption of sodium and urate. It is common in patients receiving large amounts of fluids intravenously, those with psychogenic polydipsia or SIADH. In these situations, water restriction corrects hyponatremia and hypouricemia. However, hypouricemia in patients with intracranial disease associated with cerebral salt wasting syndrome is not corrected by water restriction. Hypouricemia has no symptoms; the symptoms are those of the causal disease. However, isolated tubular hypouricemia may be associated with nephrolithiasis and acute renal failure induced by exercise in patients with mutations in either the URAT13,15-17 or GLUT925 gene. In these cases, the clinical symptoms are generalised fatigue, nausea or vomiting and diffuse abdominal discomfort; and they often appear at approximately 2 weeks after physical exercise. If the patient has been previously diagnosed with hypouricemia, its diagnosis is simple and treatment can be provided earlier. It is therefore recommended that uric acid levels be determined in routine medical examinations followed by physical exercise, especially in Asians.52 Two mechanisms have been proposed to explain acute renal failure. First, acute urate nephropathy, caused by increased urate production during exercise, culminating in its intratubular precipitation. The second mechanism is ischaemic renal aggression secondary to vasoconstriction of the renal vessels, mediated by the production of oxygen free radicals during exercise.53 It is known that uric acid is the most abundant soluble antioxidant in humans, as it preserves endothelial function in situations of oxidative stress.54 This mechanism is based on histological results showing acute tubular necrosis,55 although it should be considered only as a triggering cofactor, as acute renal failure induced by exercise has not been described in patients with xanthinuria.26 Dinour et al. have proposed a third mechanism, whereby the accumulation of anions not eliminated in patients with URAT or GLUT9 gene mutations exerts a toxic tubular effect leading to acute tubular necrosis.26 Finally, we would like to emphasise that hereditary tubular hypouricemia associated with hypertension is very rare, as only one case has been reported in the medical literature.71 KEY CONCEPTS 1. Hypouricemia is defined when plasma levels of uric acid are less than or equal to 2mg/dl.2. Differential diagnosis of hypouricemia is usually made by evaluating the fractional excretion of uric acid.3. Hypouricemia with reduced fractional excretion of uric acid is associated with defects in the production of uric acid.4. Hypouricemia with increased fractional excretion of uric acid is associated with defects during the proximal tubular transport of uric acid.5. Currently there has been progress in identifying proximal tubular transporters of uric acid and the genes that encode them.6. Hypouricemia is a biochemical marker for primary or secondary tubulopathy and other underlying illnesses.<a href="grande/10588_16025_12837_en_105881.jpg" class="elsevierStyleCrossRefs"><img src="10588_16025_12837_en_105881.jpg" alt="Schematic representation of the 4-component classical hypothesis in proximal tubular handling of urate (% filtered urate)."></img></a>Figure 1. Schematic representation of the 4-component classical hypothesis in proximal tubular handling of urate (% filtered urate).<a href="grande/10588_16025_12838_en_105882.jpg" class="elsevierStyleCrossRefs"><img src="10588_16025_12838_en_105882.jpg" alt="The exchanger URAT1 reabsorbs the urate filtered at the apical membrane of proximal tubule cells in exchange with anions transported into the tubular lumen to maintain proper electrical balance"></img></a>Figure 2. The exchanger URAT1 reabsorbs the urate filtered at the apical membrane of proximal tubule cells in exchange with anions transported into the tubular lumen to maintain proper electrical balance<a href="10588_108_12814_en_w4777107445tabla_en.doc" class="elsevierStyleCrossRefs">10588_108_12814_en_w4777107445tabla_en.doc</a>Table 1. Differential diagnosis of hypouricemia by fractional excretion of uric acid" "pdfFichero" => "P1-E515-S2784-A10588-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441355" "palabras" => array:1 [ 0 => "Transporte tubular renal de ácido úrico" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441357" "palabras" => array:1 [ 0 => "Hipouricemia" ] ] ] "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441356" "palabras" => array:1 [ 0 => "Renal tubular transport of uric acid" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441358" "palabras" => array:1 [ 0 => "Hypouricemia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:1 [ "resumen" => "Hypouricemia is defined when a serum urate concentration is less than or equal 2.0mg/dl. Differential diagnosis is made by fractional uric acid excretion with the identification of urate transporters and intracellular proteins involved in the tubular transport of uric acid. This review examines current knowledge on uric acid tubular transport and the various clinical situations of hypouricemia." ] "es" => array:1 [ "resumen" => "La hipouricemia se diagnostica cuando los niveles plasmáticos de ácido úrico son menores o iguales a 2,0 mg/dl. El diagnóstico diferencial de la hipouricemia se realiza en función de la excreción fraccional de ácido úrico, y se han identificado varios transportadores y proteínas implicados en el  manejo del ión urato en el túbulo proximal. En este artículo se revisan los conocimientos actuales sobre el manejo tubular renal del ácido úrico y  las distintas situaciones clínicas asociadas con hipouricemia." ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10588_16025_12837_en_105881.jpg" "Alto" => 502 "Ancho" => 1044 "Tamanyo" => 26030 ] ] "descripcion" => array:1 [ "en" => "Schematic representation of the 4-component classical hypothesis in proximal tubular handling of urate (% filtered urate)." ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10588_16025_12838_en_105882.jpg" "Alto" => 1173 "Ancho" => 2152 "Tamanyo" => 65778 ] ] "descripcion" => array:1 [ "en" => "The exchanger URAT1 reabsorbs the urate filtered at the apical membrane of proximal tubule cells in exchange with anions transported into the tubular lumen to maintain proper electrical balance" ] ] 2 => array:8 [ "identificador" => "mmc1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "10588_108_12814_en_w4777107445tabla_en.doc" "ficheroTamanyo" => 27136 ] "descripcion" => array:1 [ "en" => "Differential diagnosis of hypouricemia by fractional excretion of uric acid" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:71 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "García Nieto V, Luis Yanes MI, Callejón A. 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Hipouricemia y manejo renal del ácido úrico

, N.. Esparza Martínb, V.. García Nietoc

b Servicio de Nefrología, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria

c Unidad de Nefrología Pediátrica, Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife,

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new therapies to block or stimulate these transport mechanisms may become available in the coming years&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">NORMAL uric acid Plasma values and urinary excretion</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Serum urate concentrations are higher in men than in women&#46; Thus&#44; hyperuricemia is defined as the existence of values above 7mg&#47;dl in men and higher than 6mg&#47;dl in women&#46; Urate excreted in the urine accounts for approximately 70&#37; of that produced daily&#44; with the rest excreted in the faeces&#46; Normal uricosuria values in adults are 620&#177;75mg&#47;day&#46;<span class="elsevierStyleSup">1&#44;2</span> Urate elimination is best studied as an excretion index &#40;normal&#58; 0&#46;40&#177;0&#46;09mg&#47;100ml&#41;<span class="elsevierStyleSup">3</span> or preferably as fractional excretion &#40;normal&#58; 7&#46;25&#177;2&#46;98&#37;&#41;&#46;<span class="elsevierStyleSup">4&#44;5</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">PHYSIOLOGICAL AND HISTORICAL BACKGROUND OF RENAL TUBULAR HANDLING OF URIC ACID&#46; NEW DEVELOPMENTS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In the early twentieth century&#44; it was assumed that uric acid was filtered by the kidney&#44; and thus excreted in the urine&#46; However&#44; in 1950&#44; Berliner et al&#46; tried to find an explanation for the finding that uric acid clearance was lower than that of creatinine&#46; To explain this &#8220;incomprehensible phenomenon&#8221;&#44; the authors induced hyperuricemia in a group of healthy subjects by an overload of lithium carbonate&#46; Studying the clearances of inulin and urate&#44; they came to the conclusion that &#8220;urate is excreted by glomerular filtration and active tubular reabsorption&#8221;&#46;<span class="elsevierStyleSup">6</span> That same year&#44; Praetorius and Kirk described the case of a patient with a severe hypouricemia in which the clearance of uric acid was higher than creatinine&#46; This led them to assume that this individual&#8217;s kidney secreted uric acid&#46; It was the first reported case of renal tubular hypouricemia&#46;<span class="elsevierStyleSup">7</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The existence of a tubular secretion phase for uric acid was again proposed in 1957 when Gutman and Yu studied 300 patients with gout and concluded that a reduction in the tubular secretion of uric acid could explain the reduction of uricosuria found&#46;<span class="elsevierStyleSup">8</span> Four years later&#44; those same authors published their 3-component theory&#46; Uric acid circulating in the blood is passively filtered at the glomerulus&#46; It is later actively reabsorbed in the proximal tubule and then secreted into the tubular lumen&#46;<span class="elsevierStyleSup">9</span> In the early 70s&#44; Diamond and Paolino&#44; through the sequential combination of various uricosuric medications &#40;sulphinpyrazone&#44; probenecid and salicylates at high doses&#41; and pyrazinamide in healthy subjects&#44; reported the existence of a reabsorption of urate in an area distal to secretion &#40;postsecretory reabsorption&#41;&#46;<span class="elsevierStyleSup">10</span> The 3-component hypothesis had thus become 4&#46; The proportion of filtered urate reabsorbed in the proximal tubule was 99&#37;-100&#37;&#44; leaving 0&#37;-2&#37; of filtered urate in the tubular lumen&#46; Subsequently&#44; a tubular secretory phase is produced&#44; with 50&#37; of the urate initially filtered remaining in the tubular lumen&#46; Finally&#44; this leads to proximal tubular reabsorption&#44; quantified at 80&#37; of that secreted&#46; This explains how the amount of uric acid excreted in the urine is approximately 10&#37; of the amount of urate filtered &#40;Figure 1&#41;&#46; Thus&#44; defects in the tubular handling of uric acid associated with hypouricemia could be caused by isolated or combined defects in the presecretory and&#47;or postsecretory reabsorption&#44; or by an increase in tubular secretion&#46; To establish the causal mechanism&#44; pharmacological tests were used with pyrazinamide stimulus &#40;to inhibit tubular secretion&#41; and probenecid or benzbromarone &#40;to inhibit postsecretory tubular reabsorption&#41;&#46;<span class="elsevierStyleSup">11</span> Currently&#44; these tests are not usually performed in daily practice&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Knowledge of the metabolism of uric acid did not change until the arrival of new developments resulting from the application of molecular biology techniques&#46; These identified several transporters and proteins that have demonstrated the complexity of urate ion handling in the proximal tubule<span class="elsevierStyleSup">12</span> &#40;Figure 2&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The URAT1 transporter that reabsorbs the filtered urate was identified by Enomoto et al&#46; in 2002&#46;<span class="elsevierStyleSup">13</span> It is located in the apical membrane of proximal tubule cells and is encoded by the gene SLC22A12&#40;URAT1&#41;&#44; 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In 2003&#44; Jutabna et al&#46; identified a new voltage sensitive organic ion transporter&#44; the URATv1 &#40;OATv1&#41;&#44; which facilitates the exit of urate from the cell&#44;<span class="elsevierStyleSup">21</span> and which is encoded by the gene SLC2A9&#46;<span class="elsevierStyleSup">22</span> It was later called GLUT9 as it was known to belong to a family of proteins facilitating the transport of hexoses &#40;fructose&#44; glucose&#41;&#46;<span class="elsevierStyleSup">23</span> Two variants of the protein have been described&#58; a GLUT9L isoform which is expressed primarily in the basolateral membrane of the proximal tubule cells&#44; and a GLUT9S isoform which is expressed exclusively in the apical membrane of these cells&#46;<span class="elsevierStyleSup">24</span> For patients with the latter renal tubular hypouricemia&#44; the urate reabsorption reduction occurs on both sides of the renal proximal tubule cells<span class="elsevierStyleSup">25&#44;26</span> &#40;Figure 2&#41;&#46; In these patients&#44; fractional excretion of urate exceeds 150&#37;&#46;<span class="elsevierStyleSup">26</span> The heterozygous carriers have moderately reduced urate levels&#46;<span class="elsevierStyleSup">26</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">GLUT9 is considered the main regulator of urate levels in humans&#46;<span class="elsevierStyleSup">27</span> Thus&#44; it has been reported that different polymorphisms in the SLC2A9 gene influence the levels of urate over a wide range of values&#46;<span class="elsevierStyleSup">28-30</span> Therefore&#44; in the future this may be a therapeutic target in patients with gout and related cardiovascular diseases&#46;<span class="elsevierStyleSup">25</span> Also&#44; the association between certain polymorphisms of the SLC2A9 gene and the development of nephrolithiasis has been described&#46;<span class="elsevierStyleSup">31</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">However&#44; the question of renal handling of uric acid is still a complex one&#46; In 1985&#44; Guggino and Aronson suggested that pyrazinamide stimulated the tubular reabsorption of urate by a Na<span class="elsevierStyleSup">&#43;</span>-dependent cotransporter&#46;<span class="elsevierStyleSup">32</span> In other words&#44; contrary to previously thought&#44; they proposed that it inhibited tubular secretion&#46; During the following years&#44; it was confirmed that there was a link between acid and sodium reabsorption in the proximal tubule&#46;<span class="elsevierStyleSup">33</span> In 2004&#44; a molecular candidate was described for this type of cotransport&#44; SLC5A8&#44; a Na<span class="elsevierStyleSup">&#43;</span>-monocarboxylate transporter that would carry out a Na<span class="elsevierStyleSup">&#43;</span>-dependent cotransport of the monocarboxylic anions lactate&#44; butyrate&#44; nicotinate&#44; beta-hydroxybutyrate and acetoacetate&#46;<span class="elsevierStyleSup">34&#44;35</span> Interestingly&#44; the human gene SLC5A8 has been reported as a tumour suppressor&#44; whose silencing may contribute to carcinogenesis and the progression of various tumours&#46; However&#44; as shown in Figure 2&#44; SLC5A8 acts synergistically with URAT1&#46; This link between the apical tubular reabsorption of urate and the reabsorption of Na<span class="elsevierStyleSup">&#43;</span> would explain hyperuricemia induced by ketoacids in diabetic ketoacidosis&#44;<span class="elsevierStyleSup">36</span> ethanol intoxication&#44;<span class="elsevierStyleSup">37</span> treatment with pyrazinamide<span class="elsevierStyleSup">38</span> and the metabolic syndrome&#46;<span class="elsevierStyleSup">39</span> It is worth remembering that hyperinsulinemia is known to increase reabsorption of Na<span class="elsevierStyleSup">&#43;</span>&#46;<span class="elsevierStyleSup">40</span> An increase in serum concentrations of these anions&#44; once filtered&#44; would increase their reabsorption in the proximal tubule which&#44; in turn&#44; would enhance the reabsorption of urate by promoting the activity of URAT and the exchange of these anions with filtered urate&#46;<span class="elsevierStyleSup">41</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Finally&#44; excretion by the kidney of a variety of drugs and metabolites which are dicarboxylic organic anions is mediated&#44; via exchange with urate&#44; by a family of multispecific OAT organic anion transporters &#40;OAT genes&#41;&#44; which are part of the SLC22 solute transporter family&#46; Different OATs are located in both the apical &#40;OAT2&#44; OAT4&#41; and the basolateral &#40;OAT1 and OAT3&#41; membranes of the renal proximal tubules&#46;<span class="elsevierStyleSup">42</span> It has been suggested that the uricosuric effect of probenecid is due to its inhibition of OAT4&#46;<span class="elsevierStyleSup">12</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Therefore&#44; acceptance of the 4-components model &#40;Figure 1&#41; requires an anatomical separation of presecretory reabsorption&#44; tubular secretion and postsecretory reabsorption&#46; At present&#44; in the absence of detailed physiological characterisation and intrarenal location of the various human transporters listed above&#44; the maintenance of this scheme cannot be sustained&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">HYPOURICEMIA</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Hypouricemia is diagnosed when plasma levels of uric acid are less than or equal to 2&#46;0mg&#47;dl&#46;<span class="elsevierStyleSup">43</span> However&#44; Sperling proposed 2&#46;1mg&#47;dl to be used as the normal lower limit for women and 2&#46;5mg&#47;dl in men&#46;<span class="elsevierStyleSup">44</span> It is reported to occur in 0&#46;8&#37; of hospitalised patients and 0&#46;2&#37; of the general population&#46;<span class="elsevierStyleSup">45</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">An article was published in 1969 from work carried out in hospitals in Toronto &#40;Canada&#41; which examined the clinical usefulness of 1&#44;000 uric acid determinations&#46; These were not requested by the physicians responsible for the patients&#44; but the biochemists included them in the analytical results&#46;<span class="elsevierStyleSup">46</span> Serum uric acid levels below 2&#46;6mg&#47;dl were found in 44 patients &#40;4&#46;4&#37; of the sample&#41;&#46; Clinical hypouricemia was questioned in only one case&#44; and considered irrelevant in the 43 remaining cases&#46; The diagnoses of these 44 patients were mixed and none was diagnosed with the classic causes of hypouricemia&#44; such as Fanconi syndrome<span class="elsevierStyleSup">47</span> or Wilson&#39;s disease&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The differential diagnosis of hypouricemia is made based on the fractional excretion of uric acid &#40;Table 1&#41;&#46; Hypouricemia with a reduced fractional excretion of uric acid is associated with xanthinuria&#44; treatment with allopurinol&#44; neoplasms and hepatic function abnormalities&#46;<span class="elsevierStyleSup">48</span> Rasburicase treatment also produces hypouricemia with reduced fractional excretion of uric acid&#44; as it is a urolithic agent that catalyses the enzymatic oxidation of uric acid into allantoin&#44; a water soluble product easily excreted by the kidneys&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">From a nephrological point of view&#44; it is worth highlighting the hypouricemia associated with hereditary xanthinuria &#40;autosomal recessive deficiency of the xanthine oxidase enzyme&#41;&#44; as it is a severe hypouricemia of less than 1mg&#47;dl associated with a decreased uric acid fractional excretion and increased xanthine excretion&#46; The confirmation of the diagnosis is made by liver or intestinal biopsy which shows the reduced enzymatic activity&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Hypouricemia with a high fractional excretion of uric acid is mainly caused by renal tubular hypouricemia&#44; either in an isolated<span class="elsevierStyleSup">15-19&#44;25&#44;26</span> or complex tubulopathy&#44; such as Toni-Debr&#233;-Fanconi syndrome&#44; caused by various conditions such as cystinosis&#44; Lowe syndrome or heavy metal poisoning&#46; Other causes are the use of salicylates&#44; intravenous contrast media&#44; total parenteral nutrition&#44; Hodgkin&#39;s disease and other neoplasias&#44; Wilson&#39;s disease and other causes of cirrhosis&#44; diabetes mellitus and syndrome of inappropriate secretion of ADH&#46; Finally&#44; an association has been described with hyperparathyroidism&#44;<span class="elsevierStyleSup">49</span> thiazide-induced hyponatremia<span class="elsevierStyleSup">50</span> and hyperbilirubinemia<span class="elsevierStyleSup">51</span> &#40;Table 1&#41;&#46; It must also be remembered that oestrogens&#44; losartan&#44; dicumarol&#44; salicylates at high-dose and trimethoprim-sulphamethoxazole are drugs that increase uric acid excretion&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Also&#44; from a nephrological point of view&#44; the existence of hypouricemia in diabetes mellitus&#44; hypouricemia associated with hyponatremia and hypouricemia secondary to tubulopathies should be noted&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">It has been reported that patients with diabetes mellitus may have hypouricemia&#46;<span class="elsevierStyleSup">56&#44;57</span> This is observable in both type 1&#44; insulin-dependent diabetes mellitus patients<span class="elsevierStyleSup">58</span> and in type 2&#44; non-insulin-dependent patients&#46;<span class="elsevierStyleSup">59&#44;60</span> This implies that the pathophysiology must initially be connected with something common to both conditions&#46; The reduction in plasma uric acid is due to an increase in its renal clearance<span class="elsevierStyleSup">58&#44;61-63 </span>and it is only observed in patients with normal GFR levels&#46; When uricosuric stimulus tests were performed&#44; a defect in presecretory reabsorption&#44;<span class="elsevierStyleSup">68</span> postsecretory<span class="elsevierStyleSup">62</span> or a combination of both <span class="elsevierStyleSup">62&#44;64</span> were seen&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In some studies&#44; increased uricosuria has been attributed to glomerular hyperfiltration&#44;<span class="elsevierStyleSup">59&#44;60</span> therefore&#44; hypouricemia could be a marker for the onset of diabetic kidney disease&#46;<span class="elsevierStyleSup">60</span> In general&#44; though not always&#44; a positive relationship has been described between glycosuria and uricosuria&#44; therefore&#44; there would be interference between the tubular reabsorption of glucose and the tubular capacity to reabsorb urate&#46;<span class="elsevierStyleSup">61</span> Hypouricemia would therefore be likely in the case of poor control of the disease&#46; Thus&#44; the hypouricemia would be associated with poor disease control&#44; hyperfiltration or a late onset of nephropathy&#46;<span class="elsevierStyleSup">69</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Regarding the value of hypouricemia in the presence of hyponatremia&#44; hypouricemia secondary to extracellular volume expansion is associated with decreased proximal reabsorption of sodium and urate&#46; It is common in patients receiving large amounts of fluids intravenously&#44; those with psychogenic polydipsia or SIADH&#46; In these situations&#44; water restriction corrects hyponatremia and hypouricemia&#46; However&#44; hypouricemia in patients with intracranial disease associated with cerebral salt wasting syndrome is not corrected by water restriction&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Hypouricemia has no symptoms&#59; the symptoms are those of the causal disease&#46; However&#44; isolated tubular hypouricemia may be associated with nephrolithiasis and acute renal failure induced by exercise in patients with mutations in either the URAT<span class="elsevierStyleSup">13&#44;15-17</span> or GLUT9<span class="elsevierStyleSup">25</span> gene&#46; In these cases&#44; the clinical symptoms are generalised fatigue&#44; nausea or vomiting and diffuse abdominal discomfort&#59; and they often appear at approximately 2 weeks after physical exercise&#46; If the patient has been previously diagnosed with hypouricemia&#44; its diagnosis is simple and treatment can be provided earlier&#46; It is therefore recommended that uric acid levels be determined in routine medical examinations followed by physical exercise&#44; especially in Asians&#46;<span class="elsevierStyleSup">52</span> Two mechanisms have been proposed to explain acute renal failure&#46; First&#44; acute urate nephropathy&#44; caused by increased urate production during exercise&#44; culminating in its intratubular precipitation&#46; The second mechanism is ischaemic renal aggression secondary to vasoconstriction of the renal vessels&#44; mediated by the production of oxygen free radicals during exercise&#46;<span class="elsevierStyleSup">53</span> It is known that uric acid is the most abundant soluble antioxidant in humans&#44; as it preserves endothelial function in situations of oxidative stress&#46;<span class="elsevierStyleSup">54</span> This mechanism is based on histological results showing acute tubular necrosis&#44;<span class="elsevierStyleSup">55</span> although it should be considered only as a triggering cofactor&#44; as acute renal failure induced by exercise has not been described in patients with xanthinuria&#46;<span class="elsevierStyleSup">26</span> Dinour et al&#46; have proposed a third mechanism&#44; whereby the accumulation of anions not eliminated in patients with URAT or GLUT9 gene mutations exerts a toxic tubular effect leading to acute tubular necrosis&#46;<span class="elsevierStyleSup">26</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Finally&#44; we would like to emphasise that hereditary tubular hypouricemia associated with hypertension is very rare&#44; as only one case has been reported in the medical literature&#46;<span class="elsevierStyleSup">71</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">KEY CONCEPTS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">1&#46; Hypouricemia is defined when plasma levels of uric acid are less than or equal to 2mg&#47;dl&#46;</p><p class="elsevierStylePara">2&#46; Differential diagnosis of hypouricemia is usually made by evaluating the fractional excretion of uric acid&#46;</p><p class="elsevierStylePara">3&#46; Hypouricemia with reduced fractional excretion of uric acid is associated with defects in the production of uric acid&#46;</p><p class="elsevierStylePara">4&#46; Hypouricemia with increased fractional excretion of uric acid is associated with defects during the proximal tubular transport of uric acid&#46;</p><p class="elsevierStylePara">5&#46; Currently there has been progress in identifying proximal tubular transporters of uric acid and the genes that encode them&#46;</p><p class="elsevierStylePara">6&#46; Hypouricemia is a biochemical marker for primary or secondary tubulopathy and other underlying illnesses&#46;</p><p class="elsevierStylePara"><a href="grande&#47;10588&#95;16025&#95;12837&#95;en&#95;105881&#46;jpg" class="elsevierStyleCrossRefs"><img src="10588_16025_12837_en_105881.jpg" alt="Schematic representation of the 4-component classical hypothesis in proximal tubular handling of urate &#40;&#37; filtered urate&#41;&#46;"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Schematic representation of the 4-component classical hypothesis in proximal tubular handling of urate &#40;&#37; filtered urate&#41;&#46;</p><p class="elsevierStylePara"><a href="grande&#47;10588&#95;16025&#95;12838&#95;en&#95;105882&#46;jpg" class="elsevierStyleCrossRefs"><img src="10588_16025_12838_en_105882.jpg" alt="The exchanger URAT1 reabsorbs the urate filtered at the apical membrane of proximal tubule cells in exchange with anions transported into the tubular lumen to maintain proper electrical balance"></img></a></p><p class="elsevierStylePara">Figure 2&#46; The exchanger URAT1 reabsorbs the urate filtered at the apical membrane of proximal tubule cells in exchange with anions transported into the tubular lumen to maintain proper electrical balance</p><p class="elsevierStylePara"><a href="10588&#95;108&#95;12814&#95;en&#95;w4777107445tabla&#95;en&#46;doc" class="elsevierStyleCrossRefs">10588&#95;108&#95;12814&#95;en&#95;w4777107445tabla&#95;en&#46;doc</a></p><p class="elsevierStylePara">Table 1&#46; Differential diagnosis of hypouricemia by fractional excretion of uric acid</p>"
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        "resumen" => "<p class="elsevierStylePara">Hypouricemia is defined when a serum urate concentration is less than or equal 2&#46;0mg&#47;dl&#46; Differential diagnosis is made by fractional uric acid excretion with the identification of urate transporters and intracellular proteins involved in the tubular transport of uric acid&#46; This review examines current knowledge on uric acid tubular transport and the various clinical situations of hypouricemia&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara">La hipouricemia se diagnostica cuando los niveles plasm&#225;ticos de &#225;cido &#250;rico son menores o iguales a 2&#44;0 mg&#47;dl&#46; El diagn&#243;stico diferencial de la hipouricemia se realiza en funci&#243;n de&#160;la excreci&#243;n fraccional de &#225;cido &#250;rico&#44; y se han&#160;identificado varios transportadores y prote&#237;nas implicados en el&#160; manejo del i&#243;n urato en el t&#250;bulo proximal&#46; En este art&#237;culo se revisan los conocimientos actuales sobre el manejo tubular renal del &#225;cido &#250;rico y&#160; las distintas situaciones cl&#237;nicas asociadas con&#160;hipouricemia&#46;</p>"
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Article information

ISSN: 20132514
Original language: English

DOI:10.3265/Nefrologia.pre2010.Oct.10588

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2024 November	8	9	17
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2024 July	99	103	202
2024 June	126	129	255
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2024 March	99	71	170
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2023 March	152	65	217
2023 February	146	59	205
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2022 December	151	58	209
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2022 August	157	91	248
2022 July	129	78	207
2022 June	138	98	236
2022 May	171	73	244
2022 April	208	84	292
2022 March	204	107	311
2022 February	214	85	299
2022 January	173	88	261
2021 December	156	89	245
2021 November	150	74	224
2021 October	197	109	306
2021 September	169	75	244
2021 August	157	51	208
2021 July	181	45	226
2021 June	144	44	188
2021 May	235	59	294
2021 April	371	116	487
2021 March	311	109	420
2021 February	282	53	335
2021 January	195	43	238
2020 December	187	41	228
2020 November	210	42	252
2020 October	147	27	174
2020 September	187	31	218
2020 August	157	35	192
2020 July	228	46	274
2020 June	220	49	269
2020 May	211	44	255
2020 April	205	27	232
2020 March	199	50	249
2020 February	187	47	234
2020 January	213	46	259
2019 December	212	70	282
2019 November	224	49	273
2019 October	291	42	333
2019 September	288	35	323
2019 August	229	47	276
2019 July	194	63	257
2019 June	128	27	155
2019 May	204	32	236
2019 April	271	54	325
2019 March	178	71	249
2019 February	139	30	169
2019 January	141	36	177
2018 December	301	52	353
2018 November	285	33	318
2018 October	237	37	274
2018 September	301	14	315
2018 August	157	19	176
2018 July	163	20	183
2018 June	131	15	146
2018 May	170	17	187
2018 April	165	12	177
2018 March	126	14	140
2018 February	118	13	131
2018 January	138	14	152
2017 December	110	10	120
2017 November	175	18	193
2017 October	105	15	120
2017 September	106	20	126
2017 August	95	21	116
2017 July	109	20	129
2017 June	117	46	163
2017 May	170	54	224
2017 April	120	36	156
2017 March	144	34	178
2017 February	263	25	288
2017 January	96	32	128
2016 December	165	11	176
2016 November	239	22	261
2016 October	326	22	348
2016 September	536	17	553
2016 August	464	14	478
2016 July	318	19	337
2016 June	235	0	235
2016 May	250	0	250
2016 April	237	0	237
2016 March	148	0	148
2016 February	175	0	175
2016 January	185	0	185
2015 December	171	0	171
2015 November	147	0	147
2015 October	147	0	147
2015 September	123	0	123
2015 August	113	0	113
2015 July	128	0	128
2015 June	56	0	56
2015 May	90	0	90
2015 April	13	0	13

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