Renal Handling Of Uric Acid Research Articles

Hyperuricemia Subtypes Classified According to Renal Uric Acid Handling Manifesting Distinct Phenotypic and Genetic Profiles in People With Gout.

Hyperuricemia can be stratified into four subtypes according to renal uric acid handling. The aim of this study was to comprehensively describe the biologic characteristics (including genetic background) of clinically defined hyperuricemia subtypes in two large geographically independent gout cohorts. Hyperuricemia subtype was defined as renal uric acid overload (ROL), renal uric acid underexcretion (RUE), combined, or renal normal. Twenty single nucleotide polymorphisms (SNPs) previously identified as gout risk loci or associated with serum urate (SU) concentration in the East Asian population were genotyped. Weighted polygenic risk scores were calculated to assess the cumulative effect of genetic risks on the subtypes. Of the 4,873 participants, 8.8% had an ROL subtype, 60.9% RUE subtype, 23.1% combined subtype, and 7.2% normal subtype. The ROL subtype was independently associated with older age at onset, lower SU, tophi, and diabetes mellitus; RUE was associated with lower body mass index (BMI) and non-diabetes mellitus; the combined subtype was associated with younger age at onset, higher BMI, SU, estimated glomerular filtration rate (eGFR), and smoking; and the normal subtype was independently associated with older age at onset, lower SU, and eGFR. Thirteen SNPs were associated with gout with 6 shared loci and subtype-dependent risk loci patterns. High polygenic risk scores were associated with ROL subtype (odds ratio [OR] = 9.63, 95% confidence interval [95% CI] 4.53-15.12), RUE subtype (OR = 2.18, 95% CI 1.57-3.03), and combined subtype (OR = 6.32, 95% CI 4.22-9.48) compared with low polygenic risk scores. Hyperuricemia subtypes classified according to renal uric acid handling have subtype-specific clinical and genetic features, suggesting subtype-unique pathophysiologic mechanisms.

Study of Serum Uric Acid Levels in Thyroid Dysfunctions

Background: Hyperuricemia in thyroid dysfunctions has been linked to either impaired renal handling of uric acid or overproduction of uric acid. This study aimed to determine the serum uric acid levels in patients with thyroid dysfunction and to determine the link between thyroid dysfunction and hyperuricemia. Methods: This prospective and quantitative study which was conducted at Department of Biochemistry, Manipal Teaching Hospital determined the serum uric acid concentrations of 30 years or older; male or female participants diagnosed with either hypothyroidism or hyperthyroidism. T3 and T4 was determined by chemiluminiscence immunoassay (CLIA) and OCD VITROS dry chemistry analyzer was used to determine serum uric acid level. Data entry and analysis was done using SPSS version 23. Descriptive statistics using frequency with percentage and inferential statistics using non-parametric tests were used. Results: In a total of 100 participants, prevalence of hyperuricemia was 42% (31% in hypothyroidism and 11% in hyperthyroidism). The mean serum uric acid in overall participants was 6.25 ± 2.04 (6.55 ± 1.84 in hypothyroidism and 6.05 ± 1.71 in hyperthyroidism).Significant association was seen between thyroid status and hyperuricemia (p = 0.001).Also, significant difference (p = 0.02) was seen in serum uric acid between hyperthyroid and hypothyroid patients. Conclusion: Higher prevalence rate of hyperuricemia was found among hypothyroid patients than in hyperthyroid subjects, and a significant association was found between thyroid dysfunction and hyperuricemia. This indicates need for more research to further uncover the mechanisms underlying it.

Acute effect of empagliflozin on serum uric acid – a subanalysis of the EMPAG-HF trial (effects of empagliflozin on diuresis and renal function in patients with acute decompensated heart failure)

Abstract Background Elevated levels of uric acid (UA) have been associated with worsening of outcomes in cardiovascular and renal disease and may lead to gout. Patients with acute decompensated heart failure (ADHF) may develop hyperuricemia under intensified diuretic treatment. In this setting, the effect of empagliflozin on serum uric acid remains unknown. Aim/Purpose The aim of this subanalysis in patients with ADHF was to assess how additive treatment with empagliflozin influences the concentration of serum uric acid and potential related outcomes. Methods In the single-center, prospective, double-blind, placebo-controlled EMPAG-HF trial, patients with ADHF were screened and randomized within 12 hours following hospital admission to receive either empagliflozin 25 mg or placebo in addition to standard medical treatment over five days. Sixtypatients (mean age 74,7±9,9, 39% female) were enrolled and randomized 1:1 irrespective of left ventricular ejection fraction or the presence of diabetes. UA in serum was determined daily and renal handling of UA was evaluated by fractional excretion of UA (FEUA). Two-way mixed ANOVA and Wilcoxon rank-sum test were used for statistical analyses. Results The empagliflozin group comprised 30 patients and the placebo group comprised 29 patients. There were no differences in baseline patient characteristics including LVEF, NT-proBNP, eGFR, HbA1c. In the placebo group, UA increased from baseline 487.86±32.21 μmol/l to 500.38±28.37 μmol/l at day (d) 2 (p=0.045), 512.36±29.43 μmol/l at d3 (p=0.018), and 518.46±31.14 μmol/l at d4 (p=0.021). By contrast, in the empagliflozin group, UA tended to decrease compared to baseline and was significantly lower compared to placebo at d3 (436.08±23.94 vs. 512.36±29.43 μmol/l, p=0.049), d4 (423.20±24.12 vs. 518.46±31.14 μmol/l, p=0.018), and d5 (423.17±24.75 vs. 508.62±31.08 μmol/l, p=0.037). Serum UA returned to baseline levels in both groups 30 days after cessation of empagliflozin. The reduction of UA in the empagliflozin group was associated with a significant enhancement in FEUA (5.49±0.81% vs. 9.38±1.07%, p=0.004). Conclusion Our data suggest that the additive treatment with empagliflozin in patients with acute decompensated heart failure lowers the levels of serum uric acid compared to loop diuretics alone. This effect may be attributed to an improved renal elimination of UA and a better preservation of kidney function. It remains to be clarified whether this uricosuric effect of empagliflozin also contributes to its prognostic benefits in heart failure. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Department of Internal Medicine I, Division of Cardiology, Angiology and Intensive Medical Care, University Hospital Jena, Friedrich-Schiller-University, Jena, Germany) Boehringer Ingelheim Inc.

Renal lipid accumulation, oxidative stress and uric acid handling in a rodent model of obesity and metabolic syndrome

Hyperuricemia is more prevalent among people with obesity and metabolic syndrome, and is associated with adverse clinical outcomes. We hypothesized that increased renal reabsorption of uric acid (UA) in obesity...

Effect of body mass index on serum urate and renal uric acid handling responses to an oral inosine load: experimental intervention study in healthy volunteers

BackgroundHigh body mass index (BMI) is strongly associated with hyperuricaemia. It is unknown whether overweight and obesity influences serum urate primarily through increased urate production or reduced renal clearance of uric acid. The aim of this study was to determine the influence of BMI on the response to inosine, a purine nucleoside that functions as an intermediate in the purine salvage and degradation pathways.MethodsFollowing an overnight fast, 100 healthy participants without gout attended a study visit. Blood and urine samples were taken prior to and over 180 min after 1.5 g oral inosine. Serum urate and fractional excretion of uric acid (FEUA) were analysed according to high BMI (≥ 25 kg/m2) and low/normal BMI (< 25 kg/m2) groups, and according to BMI as a continuous variable.ResultsParticipants in the high BMI group (n = 52, mean BMI 30.8 kg/m2) had higher serum urate concentrations at baseline (P = 0.002) compared to those with low/normal BMI (mean BMI 21.8 kg/m2). However, the high BMI group had a smaller increase in serum urate following the inosine load (P = 0.0012). The two BMI groups had a similar FEUA at baseline (P = 0.995), but those in the high BMI group had a smaller increase in FEUA following the inosine (P = 0.0003). Similar findings were observed when analysing BMI as a continuous variable. Those with high BMI had a smaller increase in FEUA per increase in serum urate, compared to those with low BMI (P = 0.005).ConclusionsIn a fasting state, people with high BMI have elevated serum urate levels but similar FEUA values compared with those with low/normal BMI. Following a purine load, those with high BMI have an attenuated renal excretion of uric acid. These data, using an experimental method to dynamically assess human urate handling, suggest that people with high BMI have a higher renal capacity for uric acid reabsorption when fasted and following a dietary purine intake have reduced renal clearance.Trial registrationAustralia and New Zealand Clinical Trials Registry, ACTRN12615001302549, date of registration 30 November 2015.

Efficacy of different urinary uric acid indicators in patients with chronic kidney disease

BackgroundMounting studies have shown that hyperuricemia is related to kidney diseases through multiple ways. However, the application of urinary uric acid indicators in patients with reduced renal function is not clear. In this study, we aim to determine the effects of renal function on various indicators reflecting uric acid levels in patients with chronic kidney disease (CKD).MethodsAnthropometric and biochemical examinations were performed in 625 patients with CKD recruited from Dept of Nephrology of Huadong hospital affiliated to Fudan University. Multiple regression analyses were used to study correlations of the estimated glomerular filtration rate (eGFR) with serum uric acid (SUA) and renal handling of uric acid. For further study, smooth curve plots and threshold effect analyses were applied to clarify associations between renal function and uric acid levels.ResultsThe nonlinear relationships were observed between eGFR and urinary uric acid indicators. The obvious inflection points were observed in smooth curve fitting of eGFR and fractional excretion of uric acid (FEur), excretion of uric acid per volume of glomerular filtration (EurGF). In subsequent analyses where levels of eGFR< 15 mL/min/1.73m2 were dichotomized (CKD5a/CKD5b), patients in the CKD5a showed higher levels of FEur and EurGF while lower levels of urinary uric acid excretion (UUA), clearance of uric acid (Cur) and glomerular filtration load of uric acid (FLur) compared with CKD5b group (all P < 0.05). And there was no significant difference of SUA levels between two groups. On the other hand, when eGFR< 109.9 ml/min/1.73 m2 and 89.1 ml/min/1.73 m2, the resultant curves exhibited approximately linear associations of eGFR with Cur and FLur respectively.ConclusionFEur and EurGF showed significantly compensatory increases with decreased renal function. And extra-renal uric acid excretion may play a compensatory role in patients with severe renal impairment to maintain SUA levels. Moreover, Cur and FLur may be more reliable indicators of classification for hyperuricemia in CKD patients.

P0169DYSFUNCTION OF ABCG2, URATE TRANSPORTER, IS RELATED WITH UROLITHIASIS

Abstract Background and Aims Urolithiasis is one of the rapidly increasing diseases in developed countries. It has been reported that urolithiasis is related with lifestyles, diet, obesity, climate and chronic diseases including hyperuricemia, diabetes mellitus, metabolic syndrome, chronic kidney disease et cetera. Among them, hyperuricemia is the leading cause of urolithiasis. ATP–binding cassette subfamily G member 2 (ABCG2), urate transporter, excretes uric acid in the kidney and the intestinal tract and ABCG2 dysfunction increases a risk of hyperuricemia. In this study, we investigated the estimated ABCG2 function by common two dysfunctional variants, Q126X (rs72552713) and Q141K (rs2231142), in patients with urolithiasis, and we evaluated the relation between urolithiasis and ABCG2 dysfunction. Method One hundred and ninety-seven urolithiasis patients without gout (150 males and 47 females) were enrolled. Q126X totally abolishes ABCG2 function, while Q141K reduces its function by about 50%. Since these two SNPs do not link each other and two SNPs do not exist on same chromosome, these two are regarded as independent risks. Namely, based on the genotype of Q126X and Q141K, it can be divided into three categories: a full functional group, a 75% functional group and a ≦50% functional group. Serum uric acid levels and amount of urinary uric acid were measured. Renal uric acid handling of the patients was classified into renal uric acid underexcretion type or renal uric acid overload type based on uric acid clearance and amount of urinary uric acid. Stone composition was analysed, if it had been possible. Results ABCG2 function of the patients was evaluated as follows: 82 patients, ABCG2 full function (41.6%); 78 patients, 75% function (39.6%); 37 patients, ≦50% function (18.8%). 155 patients were classified into renal uric acid underexcretion type, 13 patients were classified into renal uric acid overload type and 2 patients were classified into normal type (27 patients have not had 24-hour urine biochemical test). Stone composition analysis was performed for 136 patients; calcium oxalate stone was identified in 107 patients and uric acid stone in 29 patients. In this study, 58.4 % of the patients with urolithiasis had some ABCG2 dysfunction as against 49.8 % of the healthy individuals previously reported (p=0.0246). In addition, the ratio of subjects with urolithiasis having 50% or less of ABCG2 function was higher than healthy individuals significantly (OR=1.773, p=0.007). The high ratio of ABCG2 dysfunctional patients with urolithiasis suggested that ABCG2 dysfunction is a risk factor for urolithiasis. In the patients with urolithiasis, renal uric acid underexcretion type accounted for about 90% of the patients. This means that this type accelerated urolithiasis as well as hyperuricosuria. Conclusion ABCG2 dysfunction and renal uric acid underexcretion type were suggested to be a risk factor for urolithiasis.

P5413Effect of empagliflozin as add-on therapy on serum uric acid level in patients with type 2 diabetes hospitalized for acute decompensated heart failure: a prospective randomized controlled study

Abstract Background Elevated serum uric acid (UA) level has been shown to be associated with reduced survival among patients (pts) with heart failure. Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower serum uric acid level in pts with type 2 diabetes mellitus (T2D). Empagliflozin, one of the SGLT2 inhibitors, has been shown to reduce the risk of cardiovascular mortality in T2D pts with cardiovascular disease, and involvement of UA lowering effect by empagliflozin in the reduction of cardiovascular mortality has been suggested. However, little is known about the effect of empagliflozin as add-on therapy on serum UA level in T2D pts with acute decompensated heart failure (ADHF). Purpose We sought to elucidate the effect of empagliflozin as add-on therapy on serum UA level in T2D pts with ADHF. Methods We enrolled 38 consecutive T2D pts admitted for ADHF. On admission, enrolled pts were randomly assigned in a 1:1 ratio to either empagliflozin add-on therapy (EMPA(+)) or conventional glucose-lowering therapy (EMPA(−)). All pts in EMPA(+) group received empagliflozin (10 mg/day) throughout the study period. Left ventricular ejection fraction (LVEF) was measured at baseline using echocardiography. Body weight and vital signs, such as blood pressure and heart rate, were measured, and blood and urine samples were collected at baseline and 1, 2, 3 and 7 days after randomization. Renal handling of UA was evaluated by fractional excretion of UA (FEUA). Results Twenty pts were assigned to the EMPA(+) group, and 18 pts were assigned to the EMPA(−) group. There were no significant baseline differences in LVEF, plasma brain natriuretic peptide level, body mass index, or serum creatinine level between the EMPA(+) and EMPA(−) groups. In addition, prevalence rate of hyperuricemia, serum UA level, and FEUA did not significantly differ between the two groups at baseline. However, there was significant difference in the change in serum UA level from baseline at 2, 3 and 7 days after randomization between the two groups (Figure A). As a result, serum UA level was significantly lower in the EMPA(+) group than in the EMPA(−) group at 7 days after randomization (6.2±1.8 mg/dL vs 7.8±1.8 mg/dL, p=0.0127). Moreover, FEUN of the EMPA(+) group was significantly higher at 1, 2 and 7 days after randomization (Figure B), which suggested that serum UA level was lowered in the EMPA(+) group by increased urinary excretion of UA. Figure 1 Conclusions This study demonstrated that empagliflozin as add-on therapy can lower serum UA level in T2D pts with ADHF through the effect on the urinary excretion rate of UA.

Effects of Food and Antacids on Pharmacokinetics and Pharmacodynamics of Lesinurad, a Selective Urate Reabsorption Inhibitor.

Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000mg calcium carbonate or 1600mg magnesium hydroxide/1600mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400mg oral lesinurad. Study 2 evaluated low doses of antacids (1250mg calcium carbonate or 800mg magnesium hydroxide/800mg aluminum hydroxide) on the PK and PD of 400mg lesinurad. Food did not alter the plasma AUC of lesinurad and only reduced its Cmax by 18%. In the fasted conditions, high-dose calcium carbonate reduced the Cmax and AUC of lesinurad by 54% and 38%, respectively, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced Cmax and AUC by 36% and 31%, respectively. Food enhanced the maximum serum urate (sUA)-lowering effect of lesinurad by approximately 20% despite reducing the Cmax of lesinurad. High-dose calcium carbonate decreased the urate-lowering effect approximately 20% in the first 6hours, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced the effect by 26%. Low-dose calcium carbonate or magnesium hydroxide/aluminum hydroxide in the presence of food did not significantly affect plasma lesinurad Cmax and AUC or the sUA lowering and renal handling of uric acid. In summary, study results suggest food did not meaningfully alter lesinurad PK and PD. High doses of antacids reduced lesinurad AUC up to 40% and reduced the lesinurad uric acid-lowering effect.

GLUT9 influences uric acid concentration in patients with Lesch-Nyhan disease.

Patients with deficient hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity present hyperuricemia and/or hyperuricosuria, with a variable degree of neurological manifestations. Hyperuricemia in HPRT deficiency is due to uric acid overproduction and is frequently treated with allopurinol. Renal uric acid excretion is sharply increased in these patients. In recent years, several renal tubular urate transporter single nucleotide polymorphisms (SNPs), including those of the GLUT9, ABCG2 and URAT1 genes, have been described that influence the renal handling of uric acid and modulate serum urate levels. In the present study, we analyzed whether GLUT9, ABCG2 and URAT1 gene SNPs are able to influence uric acid levels and allopurinol response in patients with HPRT deficiency. Three SNPs, URAT1 rs11231825, GLUT9 rs16890979 and ABCG2 rs2231142, previously associated in our population with hyperuricemia and gout, were analyzed in 27 patients with HPRT deficiency treated with allopurinol for at least 5years. Patients with HPRT deficiency having allele A of rs16890979 in the GLUT9 gene present with a lower serum urate concentration at diagnosis, before allopurinol treatment is instituted, and need lower allopurinol doses to maintain serum urate levels between 268 and 446μmol/L (4.5 and 7.5mg/dL). No relationship between rs2231142 in the ABCG2 gene or rs11231825 in the URAT1 gene and serum urate levels or allopurinol response was found in our patients with HPRT deficiency. GLUT9 SNPs influence the renal handling of uric acid and modulate serum urate levels and the response to treatment in patients with uric acid overproduction due to HPRT deficiency.

Urinary excretion of uric acid is negatively associated with albuminuria in patients with chronic kidney disease: a cross-sectional study

BackgroundIncreasing evidence has shown that albuminuria is related to serum uric acid. Little is known about whether this association may be interrelated via renal handling of uric acid. Therefore, we aim to study urinary uric acid excretion and its association with albuminuria in patients with chronic kidney disease (CKD).MethodsA cross-sectional study of 200 Chinese CKD patients recruited from department of nephrology of Huadong hospital was conducted. Levels of 24 h urinary excretion of uric acid (24-h Uur), fractional excretion of uric acid (FEur) and uric acid clearance rate (Cur) according to gender, CKD stages, hypertension and albuminuria status were compared by a multivariate analysis. Pearson and Spearman correlation and multiple regression analyses were used to study the correlation of 24-h Uur, FEur and Cur with urinary albumin to creatinine ratio (UACR).ResultsThe multivariate analysis showed that 24-h Uur and Cur were lower and FEur was higher in the hypertension group, stage 3–5 CKD and macro-albuminuria group (UACR> 30 mg/mmol) than those in the normotensive group, stage 1 CKD group and the normo-albuminuria group (UACR< 3 mg/mmol) (all P < 0.05). Moreover, males had higher 24-h Uur and lower FEur than females (both P < 0.05). Multiple linear regression analysis showed that UACR was negatively associated with 24-h Uur and Cur (P = 0.021, P = 0.007, respectively), but not with FEur (P = 0.759), after adjusting for multiple confounding factors.ConclusionsOur findings suggested that urinary excretion of uric acid is negatively associated with albuminuria in patients with CKD. This phenomenon may help to explain the association between albuminuria and serum uric acid.

The Association of Urinary Sodium and Potassium with Renal Uric Acid Excretion in Patients with Chronic Kidney Disease

Background/Aims: Hypertension and hyperuricemia are closely associated with an intermingled cause and effect relationship. Additionally, urinary sodium and potassium excretion is related to blood pressure. Whether or not it is associated with urinary uric acid excretion is not clear. Therefore, we aim to study the association of urinary sodium and potassium with renal uric acid excretion in patients with CKD. Methods: A cross-sectional study of 428 patients with CKD recruited from our department was conducted. All patients were divided into hypertension and non-hypertension group. In these two groups, Spearman correlation and multiple linear regression analysis were used to study the correlation of urinary sodium and potassium with renal handling of uric acid. Results: According to multiple linear regression analysis, in hypertension group, fractional excretion of sodium (FEna) was negatively correlated with 24 hour urinary uric acid (24-hUur) and uric acid clearance rate (Cur) (beta coefficients [B]=-0.066, -0.182, respectively; both P< 0.05), and positively correlated with fractional excretion of uric acid (FEur) (B=1.641, P< 0.001). Additionally, fractional excretion of potassium (FEk) was positively correlated with FEur (B=0.576, P< 0.001), but not related to 24-hUur and Cur (both P>0.05). And urinary sodium/potassium ratio (Una/k) was negatively related to 24-h Uur and Cur (B=-0.047, -0.159, both P< 0.05), and positively related to FEur (B=0.578, P< 0.05). Furthermore, FEna and FEk was still positively related to FEur in the lowest tertile of eGFR groups (both P< 0.05), but not related in the second and highest tertile of eGFR groups (all P> 0.05). In non-hypertension group, FEna was negatively correlated with 24-hUur (B=-0.589, P< 0.05), but not related to Cur and FEur (both P> 0.05). both FEk and Una/k was not related to 24-h Uur, Cur and FEur (all P> 0.05). Moreover, FEna and FEk was still not correlated with FEur in all tertiles of eGFR groups (all P> 0.05). Conclusion: We found that in patients with CKD, urinary sodium and potassium excretion is closely correlated to renal handling of uric acid, which was pronounced in hypertensive patients with low eGFR. This phenomenon may be one of the mechanisms of the relationship between hypertension and hyperuricemia. Further research is needed to confirm it. It is expected to manage hyperuricemia in terms of controlling the diet of sodium and potassium.

Uric Acid Renal Lithiasis: New Concepts.

Uric acid (UA) stones are responsible for 5-10% of the formation of all kidney stones. Recently, an association between UA stones and insulin resistance, diabetes mellitus, and obesity has been demonstrated and so the incidence has increased. The development of UA stones is dependent on several risk factors, including genetic predisposition, geographical location, dietary indiscretion, and various metabolic characteristics. UA nephrolithiasis can arise from diverse etiologies, all with distinct underlying defects converging to one or more of 3 defects of hyperuricosuria, acidic urine pH, and low urinary volume. Low urinary pH is the commonest and by far the most important factor in UA nephrolithiasis, but the reason for this defect is unknown. Patients with UA nephrolithiasis have normal acid-base parameters assessed according to conventional clinical tests. Studies have revealed that there could be an insufficient production of urinary ammonium buffer. Many transport proteins are candidate participants in urate handling, with URAT1 and GLUT9 being the best characterized to date. Because low urine pH is the most important pathogenic factor of UA stone formation, urine alkalinization is an effective intervention to reduce UA crystallization and dissolve UA stones. Key Messages: Epidemiological and metabolic studies have indicated an association between UA nephrolithiasis and insulin resistance. Some potential mechanisms include impaired ammoniagenesis caused by resistance to insulin action in the renal proximal tubule or due to substrate competition by free fatty acids. The identification of novel complementary DNA has provided an interesting insight into the renal handling of UA, including one genetic cause of renal UA wasting.

Renal Handling of Uric Acid.

Hyperuricemia occurs in 21.4% of the adult population and is associated with several conditions that increase oxidative stress and contributes to the pathogenesis of inflammatory mechanisms for the development and progression of diseases. Serum blood or urine samples of uric acid levels were used to mainly identify clinical problems, depending on the uric acid pathway alterations, which include synthesis, reabsorption or its excretion. Several proteins that act particularly as transporters (URAT1, GLUT9, 1-NPT1, 1-NPT4, OAT4, 9-MCT9, hUAT1, etc.) have been identified in the recent past involving tubular transport and clearance leading to clinical benefits. Until now, the knowledge of uric acid homeostasis centers its primary investigation on understanding molecular and genetic mechanisms, including the genetic polymorphisms that induce genetic and acquire renal tubular disorder, which increases or diminishes urate excretion.

Renal Effects of Hyperuricemia.

From a clinical point of view, uric acid has been dismissed as a cause of injury and renal progression, and the mechanisms by which uric acid directly causes renal injury have not been fully understood. Hyperuricemia is associated with metabolic syndrome, diabetes, hypertension, and kidney and cardiovascular diseases. Although it remains controversial whether hyperuricemia is a causal factor for kidney disease, kidneys play a major role in the regulation of serum uric acid levels. Similar to the management of other substances, renal uric acid management occurs mainly in the proximal tubule. The elevation of uric acid in blood is mainly due to an increase in its intake or a defect in its secretion. The mechanisms of renal damage go beyond the deposition of crystals at the tubular level; in this sense, renal damage also contributes to the production of chemotactic cytokines, cell proliferation, and inflammation, with the development of afferent arteriolopathy, glomerular hypertrophy and tubulointersticial fibrosis. Nevertheless, whether or not hyperuricemia plays a causal role or simply is a marker arising in the course of each related disorder remains unresolved. Although a strong relationship between hyperuricemia and metabolic syndrome has been established through animal and epidemiological studies, the potential pathophysiological mechanisms by which uric acid contributes to this disease state are just beginning to be explained and clarified. Key Messages: Experimental studies performed in animals have limitations due to the differences that exist between humans and other mammals in purine metabolism and in renal uric acid handling. Additional experimental studies aimed at evaluating the effects of lowering urate levels on the courses of these disorders are warranted in the future.

Influence of genetic variants on renal uric acid handling in response to frusemide: an acute intervention study

ObjectivesGenetic variation in the renal urate transporters SLC2A9 (GLUT9) and SLC22A11 (OAT4) has been reported to interact with diuretics to increase the risk of developing gout. The aim of this...

Renal clearance of uric acid is linked to insulin resistance and lower excretion of sodium in gout patients.

Inefficient renal excretion of uric acid is the main pathophysiological mechanism for hyperuricemia in gout patients. Polymorphisms of renal tubular transporters linked with sodium and monosaccharide transport have yet to be demonstrated. We intended to evaluate the impact of insulin resistance, evaluated with the homeostasis model assessment (HOMA), through a transversal study of non-diabetic patients with gout, with normal renal function, not treated with any medication but colchicine as prophylaxis. One hundred and thirty-three patients were evaluated. Clearance of uric acid was inversely correlated with insulin resistance and directly correlated with fractional excretion of sodium. In multivariate analysis, hypertension and hyperlipidemia, in addition to insulin resistance and fractional excretion of sodium, were associated with renal clearance of uric acid. HOMA cutoff for efficient versus inefficient renal handling of uric acid was 2.72, close to that observed in studies of reference population. The impact of insulin resistance and renal handling of sodium on renal clearance of uric acid may help to explain why hyperuricemia is more commonly associated with diabetes and hypertension.

Renal handling of uric acid after kidney donation: a concern for further study

Renal handling of uric acid after kidney donation: a concern for further study

Clinical and Functional Characterization of URAT1 Variants

Idiopathic renal hypouricaemia is an inherited form of hypouricaemia, associated with abnormal renal handling of uric acid. There is excessive urinary wasting of uric acid resulting in hypouricaemia. Patients may be asymptomatic, but the persistent urinary abnormalities may manifest as renal stone disease, and hypouricaemia may manifest as exercise induced acute kidney injury. Here we have identified Macedonian and British patients with hypouricaemia, who presented with a variety of renal symptoms and signs including renal stone disease, hematuria, pyelonephritis and nephrocalcinosis. We have identified heterozygous missense mutations in SLC22A12 encoding the urate transporter protein URAT1 and correlate these genetic findings with functional characterization. Urate handling was determined using uptake experiments in HEK293 cells. This data highlights the importance of the URAT1 renal urate transporter in determining serum urate concentrations and the clinical phenotypes, including nephrolithiasis, that should prompt the clinician to suspect an inherited form of renal hypouricaemia.

Renal Secretion of Uric Acid by Organic Anion Transporter 2 (OAT2/SLC22A7) in Human

The physiological function of organic anion transporter OAT2 (SLC22A7) remains unclear, but since OAT2 transports purine derivatives, it may be involved in renal handling of uric acid, the final metabolite of purine derivatives. In the present study, we studied uric acid transport in stably OAT2-expressing HEK293 cells (HEK293/OAT2). OAT2 mediated uptake, but not efflux, of [(14)C]uric acid. Uric acid transport was saturable with K(m) of 1168+/-335 muM (mean and S.E.M.) and V(max) of 2.57+/-0.350 nmol/min/mg protein. The [(14)C]uric acid uptake was sensitive to Cl(-) and was enhanced at acidic pH. In cis-inhibition assay, [(14)C]uric acid uptake was inhibited by several mono- or dicarboxylic acids, but it was not trans-stimulated by any of the compounds tested. The pattern of inhibition of OAT2-mediated uric acid transport by various drugs was different from that of OAT1- or OAT3-mediated transport. Furthermore, OAT2-mediated transport of uric acid was inhibited by an antiuricosuric drug, pyrazinecarboxylic acid. These results revealed distinct characteristics of uric acid transport via OAT2 compared with other uric acid transporters, suggesting that OAT2 plays a role in renal uric acid uptake from blood as a first step of tubular secretion. OAT2 may therefore be a potential target for regulating serum uric acid level.