Role Of Hyperuricemia Research Articles

Serum Uric Acid and Progression of Kidney Disease: A Longitudinal Analysis and Mini-Review.

BackgroundIncreasing evidence supports the association between hyperuricemia and incident chronic kidney disease (CKD); however, there are conflicting data regarding the role of hyperuricemia in the progression of CKD. This study retrospectively assessed the longitudinal association between uric acid (UA) level and CKD progression in a Chinese population lived in Taiwan.MethodsPatients with physician diagnosis of hyperuricemia or receiving urate-lowering therapy between 2003 and 2005 were identified in the electronic medical records (EMR) of a tertiary medical center and were followed up until December 31, 2011. Patients were divided into four UA categories at the cut-off 6, 8, and 10 mg/dL. CKD progression was estimated by the change of estimated glomerular filtration rate (eGFR) in the linear mixed models. Kidney failure was defined as an eGFR less than 15 mL/min/1.73 m2 or requiring renal replacement therapy.ResultsA total of 739 patients were analyzed. In the full-adjusted model, patients with a baseline UA level ≥6 mg/dL had greater decline in eGFR ((β = -9.6, 95% CI -16.1, -3.1), comparing to those with a UA level less than 6 mg/dL. When stratifying patients into four UA categories, all three hyperuricemia categories (UA6-8, 8–10, ≥10 mg/dL) associated with a greater decline in eGFR over the follow-up period with an increasing dose-response, comparing to the lowest UA category. The risk of progression to renal failure increased 7% (hazard ratio 1.07, 95% CI 1.00, 1.14) for each 1mg/dL increase in baseline UA level. The influences of hyperuricemia on eGFR decline and the risk of kidney failure were more prominent in patients without proteinuria than those with proteinuria.ConclusionOur study showed a higher uric acid level is associated with a significant rapid decline in eGFR and a higher risk of kidney failure, particularly in patients without proteinuria. Our findings suggest hyperuricemia is a potential modifiable factor of CKD progression.

Sustained kidney biochemical derangement in treated experimental diabetes: a clue to metabolic memory

The occurrence of biochemical alterations that last for a long period of time in diabetic individuals even after adequate handling of glycemia is an intriguing phenomenon named metabolic memory. In this study, we show that a kidney pathway is gradually altered during the course of diabetes and remains persistently changed after late glycemic control in streptozotocin-induced diabetic rats. This pathway comprises an early decline of uric acid clearance and pAMPK expression followed by fumarate accumulation, increased TGF-β expression, reduced PGC-1α expression, and downregulation of methylation and hydroxymethylation of mitochondrial DNA. The sustained decrease of uric acid clearance in treated diabetes may support the prolonged kidney biochemical alterations observed after tight glycemic control, and this regulation is likely mediated by the sustained decrease of AMPK activity and the induction of inflammation. This manuscript proposes the first consideration of the possible role of hyperuricemia and the underlying biochemical changes as part of metabolic memory in diabetic nephropathy development after glycemic control.

Uric Acid for Cardiovascular Risk: Dr. Jekyll or Mr. Hide?

Uric acid (UA) is a potent endogenous antioxidant. However, high concentrations of this molecule have been associated with cardiovascular disease (CVD) and renal dysfunction, involving mechanisms that include oxidative stress, inflammatory processes, and endothelial injury. Experimental and in vitro results suggest that this biomarker behaves like other antioxidants, which can shift from the physiological antioxidant action to a pro-oxidizing effect according to their level and to microenvironment conditions. However, data on patients (general population or CAD cohorts) are controversial, so the debate on the role of hyperuricemia as a causative factor for CVD is still ongoing. Increasing evidence indicates UA as more meaningful to assess CVD in women, even though this aspect needs deeper investigation. It will be important to identify thresholds responsible for UA “biological shift” from protective to harmful effects in different pathological conditions, and according to possible gender-related differences. In any case, UA is a low-tech and inexpensive biomarker, generally performed at patient’s hospitalization and, therefore, easily accessible information for clinicians. For these reasons, UA might represent a useful additive tool as much as a CV risk marker. Thus, in view of available evidence, progressive UA elevation with levels higher than 6 mg/dL could be considered an “alarm” for increased CV risk.

Uric acid and xanthine oxidase in heart failure - Emerging data and therapeutic implications.

The role of hyperuricaemia as cardiovascular risk factor has exhaustingly been debated for decades. While the association of elevated uric acid (UA) levels with increased mortality risk as convincingly been shown, the question whether UA is independently predictive of just a related effect within a more complex risk factor profile (including metabolic, inflammatory and haemodynamic risk factors) is still a matter of dispute. In heart failure the independent prognostic and functional impact of elevated UA has not only been shown but also the pathophysiologic mechanism(s) and the potential of targeted therapeutic interventions have been investigated in some detail. The emerging picture suggests the increased activity of the enzyme xanthine oxidase (XO) with corresponding increased production of free oxygen radical (ROS) as a main underlying principle with the resulting increase in UA levels being mostly a marker of this up-regulated pathway. While this concept will not diminish the value of UA as a prognostic marker, it provides the basis for a novel metabolic treatment option and the means to identify those patients most eligible for this tailored therapy. This review will summarize the recent evidence on XO as a novel and promising therapeutic target in heart failure.

Soluble monosodium urate, but not its crystal, induces toll like receptor 4-dependent immune activation in renal mesangial cells

BackgroundUric acid has emerged as a novel and potential modifiable risk factor for the incidence and progression of kidney diseases, however, the deteriorate effect of uric acid on renal mesangial cells remains unclear. The present study is to examine the immune activation of soluble and crystal forms of uric acid in human mesangial cells. MethodsWe stimulated primary human mesangial cells (HMCs) with increasing concentrations (from 50 to 200μg/ml) of soluble monosodium urate (MSU) or MSU crystals. We examined interleukin (IL)-1β protein expression levels in cell culture by ELISA. The stimulated HMCs were further stimulated with soluble MSU or MSU crystals at 200μg/ml with or without the pre-incubation of toll like receptor (TLR) 4 inhibitor TAK242 (1μM). TLR4, nod-like receptor protein (NLRP3, also known as NALP3), IL-1β, human leukocyte antigen (HLA)-DR and CD40 were examined by Realtime-PCR, Western blot and ELISA, respectively. ResultsWe found that both soluble MSU and MSU crystals increased IL-1β protein expression levels in dose-dependent fashion. Soluble MSU significantly enhanced the expression of TLR4, NLRP3, IL-1β, HLA-DR and CD40 while MSU crystals only upregulated the expression of TLR4 and IL-1β. TLR4 inhibitor TAK242 significantly blocked the up-regulation of NLRP3, IL-1β, HLA-DR and CD40 induced by soluble MSU while no TAK242 suppression effect on MSU crystals induced IL-1β up-regulation was found. ConclusionsOur results suggested that soluble MSU, but not MSU crystals, induce NLRP3, IL-1β, HLA-DR and CD40 upregulation in a TLR4-dependent manner. These findings indicate that soluble MSU may play a pathological role in hyperuricemia induced renal mesangial injury.

Hyperuricemia: A risk factor beyond gout

A global epidemiological transition in the prevalence of noncommunicable diseases is taking place due to the emergence of behavioral and metabolic risk factors. A renewed interest in the role of serum uric acid as a risk factor has been generated and a crossover from rheumatology to composite of cardiovascular disorders is taking place. Hyperuricemia (HU) is defined as serum urate level > 6.8 mg/dl that is, the limit of urate solubility at physiological temperature and pH. The prevalence of HU and its complications have increased globally in the past decades. It is an indicator of a widespread transition in lifestyle. The positive association between serum uric acid and hypertension, coronary artery disease, stroke, heart failure, renal failure, and preeclampsia has been recognized. Evidence suggests that elevated serum uric acid is strongly associated with and predictive of insulin resistance and metabolic syndrome. The role of HU in the pathogenesis of cardiovascular and renal diseases involves effects on the endothelial function, oxidative metabolism, and platelet aggregation. Among the constellation of established atherosclerotic cardiovascular risk factors HU has an additive or synergistic impact on the outcomes. As an independent risk factor for cardiovascular and related diseases, the role of HU has been extensively debated for many years. Besides being a biomarker and risk factor, HU is also emerging a target for the prevention of atherosclerotic cardiovascular diseases. In most of the patients, with asymptomatic HU, treatment is not advocated to reduce cardiovascular risk. Currently, no guidelines and recommendations have been updated in the pharmacological management of asymptomatic HU. It will be particularly important to design large, long-term studies that would determine the effects of urate-lowering therapy on cardiovascular disease.

Hyperuricemia and deterioration of renal function in autosomal dominant polycystic kidney disease.

BackgroundThe role of hyperuricemia in disease progression of autosomal dominant polycystic kidney disease (ADPKD) has not been defined well. We investigated the association of serum uric acid (sUA) with renal function and the effect of hypouricemic treatment on the rate of renal function decline.MethodsThis is a single-center, retrospective, observational cohort study. A total of 365 patients with ADPKD who had estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 and who were followed up for > 1 year were included in our analysis. Hyperuricemia was defined by a sUA level of ≥ 7.0 mg/dL in male and ≥ 6.0 mg/dL in female or when hypouricemic medications were prescribed.ResultsHyperuricemia was associated with reduced initial eGFR, independent of age, sex, hypertension, albuminuria, and total kidney volume. During a median follow-up period of over 6 years, patients with hyperuricemia showed a faster annual decline in eGFR (−6.3% per year vs. −0.9% per year, p = 0.008). However, after adjusting for age, sex, hypertension and initial eGFR, sUA was no longer associated with either annual eGFR decline or the development of ESRD. Among 53 patients who received hypouricemic treatment, the annual eGFR decline appeared to be attenuated after hypouricemic treatment (pretreatment vs. posttreatment: −5.3 ± 8. 2 vs. 0.2 ± 6.2 mL/min/1.73 m2 per year, p = 0.001 by Wilcoxon signed-rank test).ConclusionsAlthough hyperuricemia was associated with reduced eGFR, it was not an independent factor for renal progression in ADPKD. However, the correction of hyperuricemia may attenuate renal function decline in some patients with mild renal insufficiency.

Serum uric acid and chronic kidney disease: the role of hypertension.

BackgroundThere are inconsistent findings on the role of hyperuricemia as an independent risk factor for chronic kidney disease (CKD). Hypertension has been implicated as a factor influencing the association between serum uric acid and CKD. In this population-based study we investigated the association between serum uric acid and decline in renal function and tested whether hypertension moderates this association.MethodsWe included 2601 subjects aged 55 years and over from the Rotterdam Study. Serum uric acid and estimated glomerular filtration rate (eGFR) were assessed at baseline. After average 6.5 years of follow-up, second eGFR was assessed. CKD was defined as eGFR<60 ml/min/1.73 m2. All associations were corrected for socio-demographic and cardiovascular factors.ResultsEach unit (mg/dL) increase in serum uric acid was associated with 0.19 ml/min per 1.73 m2 faster annual decline in eGFR. While the association between serum uric acid and incidence of CKD was not significant in our study population (Hazard Ratio: 1.12, 95% confidence interval [CI]: 0.98–1.28), incorporating our results in a meta-analysis with eleven published studies revealed a significant association (Relative Risk: 1.18, 95%CI: 1.15–1.22). In the stratified analyses, we observed that the associations of serum uric acid with eGFR decline and incident CKD were stronger in hypertensive subjects (P for interaction = 0.046 and 0.024, respectively).ConclusionsOur findings suggest that hyperuricemia is independently associated with a decline in renal function. Stronger association in hypertensive individuals may indicate that hypertension mediates the association between serum uric acid and CKD.

Increased Serum Uric Acid as a Risk Factor for Cardiovascular Diseases

Uric acid, the final product of purine catabolism, tends to accumulate in humans due to the lack of the enzyme uricase. Serum uric acid (SUA) higher than 7 mg/dL is defined as hyperuricemia, the main established risk factor for the development of gout. Nonetheless, since the nineteenth century evidence has increased about the involvement of SUA in the development of cardiovascular diseases. This review will analyze the evidence supporting the existence of a causal relationship between hyperuricemia and the most common cardiovascular disorders such as hypertension, coronary artery disease, heart failure and stroke. We will also review the strength of the relationship as well as the role of hyperuricemia as a new risk factor for cardiovascular diseases. Finally we will discuss if treating hyperuricemia could have a role in terms of cardiovascular prevention.

AB0630 Gout and hypertension. role of hyperuricemia in the development of hypertension.

BackgroundThe most of patients with gout have various associated diseases, from which hypertension (HTN) has an important prognostic value. The role of hyperuricemia (HUE) in the development of HTN remains...

Role of Hyperuricemia in Cardiorenal Syndrome

Role of Hyperuricemia in Cardiorenal Syndrome

Association of Hyperuricemia With Carotid Intima-Media Thickness, Albuminuria, Diabetes, Hypertension in Chronic Renal Failure

Background: Carotid artery intima-media thickness (CAIMT) measured by B-mode ultrasonography is widely used as a surrogate marker atherosclerosis. Hyperuricemia is also a well recognized risk factor for cardiovascular diseases. This study was done to find out the role of hyperuricemia on CAIMT and albuminuria, diabetes and hypertension in chronic renal failure (CRF) patients. Methods: 132 CRF patients and 66 age and sex matched healthy controls were included in this study. Out of 132 CRF patients, 35 were hyperuricemic. CAIMT were measured by B-mode ultrasonography. Statistical analyses were done by SPSS (Statistical package for the social Sciences) soft ware (window version 17.0). Results: Hyperuricemia was independently correlated with CAIMT in CRF patients (P = 0.018). CRF patients with hyperuricemia had significantly higher CAIMT compared to CAIMT of CRF patients without hyperuricemia (P value &lt; 0.001) and healthy controls (P &lt; 0.001). In hyperuricemic CRF patients, prevalence of hypertension (P &lt; 0.001) and diabetes (P = 0.007) was significantly higher than non-hyperuricemic CRF patients. Conclusions: Hyperuricemia is independently responsible for increased thickening of Carotid artery intima media thickness and also associated with higher level of albuminuria, and higher prevalence of hypertension and diabetes in CRF patients. doi:10.4021/wjnu14w

Study of an association of gout and metabolic syndrome

The paper considers the problem of comorbidity of gout and metabolic syndrome. It gives the data of the authors' study that has revealed the high prevalence of metabolic syndrome in patients with primary chronic gout, as well as a substantially higher cardiovascular risk in patients with the concomitance of these diseases. A role of hyperuricemia as an independent cardiovascular risk factor is demonstrated

Serum uric acid levels predict incident nonalcoholic fatty liver disease in healthy Korean men

The objective of the study was to assess the prospective association between serum uric acid levels and incident nonalcoholic fatty liver disease in a cohort of healthy Korean men. A cohort study was performed on 5741 Korean men, 30 to 59 years of age, with no evidence of fatty liver disease on liver ultrasound and with no major risk factors for liver disease at baseline. Study participants were followed in annual or biennial health examinations between 2002 and 2008. The presence of fatty liver was determined at each examination by ultrasound. Cox proportional hazards models were used to evaluate the association of baseline and time-dependent levels of serum uric acid with incident fatty liver, adjusted for potential confounders. During 23 995 person-years of follow-up, 1717 participants developed fatty liver on ultrasound examination. After adjustment for age, body mass index, smoking, and alcohol intake, the hazard ratios (95% confidence intervals) for incident fatty liver comparing quartiles 2 to 4 of serum uric acid to quartile 1 were 1.17 (1.01-1.37), 1.28 (1.11-1.48), and 1.51 (1.31-1.73), respectively ( P for trend = .001). The adjusted hazard ratio comparing participants with hyperuricemia (serum uric acid ≥7.0 mg/dL) to those with normouricemia (<7.0 mg/dL) was 1.29 (1.14-1.46). A graded and statistically significant association persisted after adjusting for other cardiometabolic factors and also in time-dependent models. Serum uric acid was an independent risk factor of incident fatty liver detected by ultrasonography. Additional research should clarify the mechanisms underlying this association and the role of hyperuricemia in the development of fatty liver.

Hyperuricemia in Obese Children and Adolescents: The Relationship with Metabolic Syndrome

The prevalence of hyperuricemia in obese children and adolescents and its association with metabolic syndrome are largely unknown. The objective of our study was to characterize hyperuricemia in relation to metabolic syndrome in Japanese children and adolescents with obesity. Between 2005 and 2008, we performed a cross-sectional study of 1,027 obese children and adolescents aged 6–14 years. Based on the reference value of serum uric acid we had established previously, hyperuricemia was defined as one standard deviation over the mean value at each age. The diagnosis of metabolic syndrome was made based on the Japanese criteria for children. A total of 213 children and adolescents (20.7%) was found to have hyperuricemia. The prevalence of hyperuricemia was significantly higher in the male gender and older age group. Sixty-five out of 213 subjects with hyperuricemia (30.5%) had metabolic syndrome, whereas 111 out of 814 subjects without hyperuricemia (13.6%) had metabolic syndrome. The most common abnormal component of metabolic syndrome was triglyceride, followed by diastolic blood pressure, systolic blood pressure, fasting blood glucose, and HDL-cholesterol. Such a tendency was almost identical between the two groups. We concluded that considering the association between hyperuricemia and metabolic syndrome in obese Japanese children and adolescents, the role of hyperuricemia in metabolic syndrome should receive more attention, beginning in early childhood.

The role of hyperuricemia in vascular disorders

The role of uric acid as a mediator of vascular damage is not a new idea but has only recently gained widespread acceptance. Uric acid has previously been viewed as a benign solute in serum until it exceeds its saturation level. Others have viewed it as an important antioxidant. These opinions have given way to strong epidemiologic evidence that uric acid elevation may damage endothelial cells and cause significant medical problems. The comorbidities associated with gout include hypertension, renal failure, obesity and diabetes. Multiple large epidemiologic studies cited in this review show that uric acid itself may play an important role in initiating the vascular endothelial dysfunction associated with this cluster of medical problems and ultimately lead to stroke, coronary artery disease and chronic kidney disease. These studies are supported by experiments in animals demonstrating how uric acid can gain entrance into cells and function as a 'pro-oxidant'. Uric acid has been long recognized as the cause of gouty arthritis and kidney stones. There is mounting evidence that it may also have an important role in the development of vascular conditions such as coronary heart disease, stroke and kidney disease. These findings have important implications for the way we view asymptomatic hyperuricemia and for future therapeutic interventions.

The role of hyperuricemia and gout in kidney and cardiovascular disease

Elevated serum urate levels are recognized as leading to gouty arthritis, tophi formation, and uric acid kidney stones. While serum urate elevations have long been associated with renal disease, they are not usually considered to have a causal role in kidney dysfunction. However, recent epidemiologic studies have identified serum urate elevations as an independent risk factor for chronic kidney disease. Hyperuricemia has also been found to be an independent risk factor for cardiovascular disease and hypertension. An animal model of mild hyperuricemia has shed new light on a potential mechanism of microvascular changes leading to endothelial dysfunction, a precursor to both coronary artery disease and hypertension. Additional animal studies and recent epidemiologic findings have provided further evidence that soluble urate is a risk factor for nonarticular disease.

Xanthine oxidase inhibitors from the leaves of Lagerstroemia speciosa (L.) Pers.

Xanthine oxidase (XOD) is a key enzyme playing a role in hyperuricemia, catalyzing the oxidation of hypoxanthine to xanthine and then to uric acid. This study aimed to identify the XOD inhibitors from the leaves of Lagerstroemia speciosa (L.) Pers. (Lythraceae), which was traditionally used as a folk medicine in the Philippines. Using a bioassay-guided fractionation technique, two active compounds were isolated from the aqueous extracts of the Lagerstroemia speciosa leaves, namely valoneic acid dilactone (VAD) and ellagic acid (EA). The result demonstrated that the XOD-inhibitory effect of VAD was a stronger than that of allopurinol, a clinical drug used for XOD inhibitor, with a non-competitive mode for the enzyme with respect to xanthine as the substrate. These results may explain and support the dietary use of the aqueous extracts from Lagerstroemia speciosa leaves for the prevention and treatment of hyperuricemia.

Decreases in serum uric acid by amelioration of insulin resistance in overweight hypertensive patients: effect of a low-energy diet and an insulin-sensitizing agent

Background Hyperuricemia and hyperinsulinemia/insulin resistance are commonly seen in obese subjects and hypertensive patients. To clarify whether the insulin resistance plays a role in hyperuricemia, we investigated alterations in serum uric acid (UA) concentrations during treatment with a low-energy diet or an insulin-sensitizing agent in overweight hypertensive patients. Methods Twenty-eight overweight hypertensive patients (14 men and 14 women, mean age 61 ± 2 years) were assigned to a weight reduction program with a low-energy diet (3360 kJ/day for 3 weeks, n = 14) and to treatment with troglitazone (200 mg twice daily for 8 weeks, n = 14). Measurements of body weight, blood pressure (BP), serum UA, and a 75-g oral glucose tolerance test were performed at baseline and the end of the intervention periods. Results Body weight and BP decreased significantly in the diet group but not in the troglitazone group at the end of the intervention periods. Levels of blood glucose, plasma insulin, and homeostasis model assessment–insulin resistance index (HOMA-R) improved similarly in the two groups. Serum UA concentration decreased by treatment both in the diet (0.4 ± 0.2 mg/dL, P < .05) and troglitazone groups (1.0 ± 0.2 mg/dL, P < .001). Conclusions The amelioration of insulin resistance by either a low-energy diet or troglitazone decreased the serum UA level in overweight hypertensive patients. Insulin resistance or hyperinsulinemia, independent of body weight and BP, may play an important role in UA metabolism in multiple risk factor syndrome.

The Role of Hyperuricemia in the Increased Cytokine Production After Lipopolysaccharide Challenge in Neutropenic Mice

AbstractPatients with severe granulocytopenia are more susceptible to severe infections and sepsis. Proinflammatory cytokines such as tumor necrosis factor-α (TNF ), interleukin-1α (IL-1α), and IL-1β play an important role in the pathophysiology of sepsis. The profile of these proinflammatory cytokines after lipopolysccharide (LPS) challenge in cyclophosphamide-induced neutropenic mice was assessed, and possible mechanisms responsible for the modified cytokine production were studied. After LPS, both circulating concentrations of TNF and IL-1α in neutropenic mice were 50% to 200% higher than those of controls, whereas IL-1β concentrations were not modified. The kinetics of cytokine production were similar in neutropenic and control animals. The susceptibility of neutropenic mice to an LPS challenge was increased. The observed overproduction of TNF and IL-1α was not due to a direct effect of cyclophosphamide treatment. Because circulating concentrations of uric acid were increased in the neutropenic mice, the effect of hypouricemic treatment with allopurinol and sodium bicarbonate was investigated; such treatment in neutropenic mice challenged with LPS was followed by an improved survival and a reduced proinflammatory cytokine production towards the concentrations in control mice. Hyperuricemia induced by repeated administrations of uric acid in normal mice led to an increased TNF production after LPS. In conclusion, neutropenic mice respond with enhanced cytokine production and increased susceptibility to an LPS challenge, and hyperuricemia probably plays an important role in this phenomenon.