Serum uric acid (SUA) levels discriminating across the different strata of cardiovascular risk is still unknown. By utilizing a large population-based database, we assessed the threshold of SUA that ...increases the risk of total mortality and cardiovascular mortality (CVM). The URRAH study (Uric Acid Right for Heart Health) is a multicentre retrospective, observational study, which collected data from several large population-based longitudinal studies in Italy and subjects recruited in the hypertension clinics of the Italian Society of Hypertension. Total mortality was defined as mortality for any cause, CVM as death due to fatal myocardial infarction, stroke, sudden cardiac death, or heart failure. A total of 22 714 subjects were included in the analysis. Multivariate Cox regression analyses identified an independent association between SUA and total mortality (hazard ratio, 1.53 95% CI, 1.21–1.93) or CVM (hazard ratio, 2.08 95% CI, 1.146–2.97; P<0.001). Cutoff values of SUA able to discriminate total mortality (4.7 mg/dL 95% CI, 4.3–5.1 mg/dL) and CVM status (5.6 mg/dL 95% CI, 4.99–6.21 mg/dL) were identified. The information on SUA levels provided a significant net reclassification improvement of 0.26 and of 0.27 over the Heart Score risk chart for total mortality and CVM, respectively (P<0.001). Sex-specific cutoff values for total mortality and CVM were also identified and validated. In conclusion, SUA levels increasing the risk of total mortality and CVM are significantly lower than those used for the definition of hyperuricemia in clinical practice. Our data provide evidence of a cardiovascular SUA threshold that might contribute in clinical practice to improve identification of patients at higher risk of CVM.
Renal proximal tubular cells (PTECs) participate in several mechanisms of innate immunity, express toll‐like receptors (TLRs), and proinflammatory cytokines. Hyperuricemia may be a promoter of ...inflammation and renal damage. Angiotensin II (Ang II) modulate immune and inflammatory responses in renal tubular cells. With the aim to evaluate the effect of uric acid (UA) and Ang II on oxidative stress and inflammation mediated by toll‐like receptor 4 (TLR4) activation in human PTECs, human kidney 2 (HK2) were incubated for 24 hr with UA (12 mg/dl) and Ang II (10
−7 M). HK2 were pretreated with an antagonist of TLR4 (TAK 242), valsartan or losartan. The genic expression of TLR4, monocyte chemoattractant protein‐1 (MCP1), and Nox4 was quantified with reverse transcription polymerase chain reaction, proteins were evaluated with Western blot. The incubation of HK2 either with UA or with Ang II determines an increased expression of TLR4, production of proinflammatory cytokines as MCP1 and pro‐oxidants as Nox4 (
p < 0.05). TAK 242 attenuates the expression of MCP1 induced both by UA and Ang II. Valsartan attenuated all the effects we described after exposure to Ang II but not those observed after UA exposure. At variance, pretreatment with losartan, which inhibits UA internalization, attenuates the expression of TLR4, MCP1, and Nox4 in cells previously treated with UA, Ang II, and UA plus Ang II. Proinflammatory pathways are induced in an additive manner by UA and Ang II (
p < 0.05) and might be mediated by TLR4 in PTECs. Renin–angiotensin–aldosterone system (RAAS) activation, hyperuricemia, and innate immunity interplay in the development of chronic tubular damage and the interaction of several nephrotoxic mechanisms blunt the protective effect of RAAS inhibition.
Proinflammatory pathways are induced in an additive manner by uric acid (UA) and angiotensin II (Ang II; p < 0.05) and might be mediated by toll‐like receptor 4 (TLR4) in renal proximal tubular cells (PTECs). Valsartan attenuated all the effects we described after exposure to Ang II but not those observed after UA exposure. At variance, pretreatment with losartan, which inhibits UA internalization, attenuates the expression of TLR4, MCP1, and Nox4 in cells previously treated with UA, Ang II, and UA plus Ang II. Renin–angiotensin–aldosterone system (RAAS) activation, hyperuricemia, and innate immunity interplay in the development of chronic tubular damage and the interaction of several nephrotoxic mechanisms blunts the protective effect of RAAS inhibition.
Epidemiological studies show that hyperuricemia independently predicts the development of chronic kidney disease (CKD) in individuals with normal kidney function both in the general population and in ...subjects with diabetes. As a matter of fact, an unfavorable role of uric acid may somewhat be harder to identify in the context of multiple risk factors and pathogenetic mechanisms typical of overt CKD such as proteinuria and high blood pressure. Although the discrepancy in clinical results could mean that urate lowering treatment does not provide a constant benefit in all patients with hyperuricemia and CKD, we believe that the inconsistency in the results from available meta-analysis is mainly due to inadequate sample size, short follow-up times and heterogeneity in study design characterizing the randomized controlled trials included in the analyses. Therefore, available data support the view that hyperuricemia has a damaging impact on kidney function, while preliminary evidence suggests that treatment of so-called asymptomatic hyperuricemia may be helpful to slow or delay the progression of chronic kidney.
Recently, there has been a growing interest in epidemiological and clinical studies supporting a pathogenetic role of fructose in cardio-metabolic diseases, especially in children and adolescents. In ...the present review, we summarize experimental data on the potential biological mechanisms linking fructose and uric acid in the development of insulin resistance, metabolic syndrome, obesity, diabetes, hypertension, non-alcoholic fatty liver disease and chronic renal disease, thereby contributing to an increase in cardiovascular risk at pediatric age.
In recent years, following the publication of results from several RCTs, first on cardiovascular and more recently on renal outcomes, SGLT2is have become the standard of care to prevent diabetic ...kidney disease and slow its progression. This narrative review focuses on biological mechanisms, both renal and extrarenal, underlying kidney protection with SGLT2is. Furthermore, data from cardiovascular as well as renal outcome trials, mostly conducted in diabetic patients, are presented and discussed to provide an overview of current uses as well as the future therapeutic potential of these drugs.
Mild hyperuricemia has been linked to the development and progression of tubulointerstitial renal damage. However the mechanisms by which uric acid may cause these effects are poorly explored. We ...investigated the effect of uric acid on apoptosis and the underlying mechanisms in a human proximal tubule cell line (HK-2). Increased uric acid concentration decreased tubule cell viability and increased apoptotic cells in a dose dependent manner (up to a 7-fold increase, p<0.0001). Uric acid up-regulated Bax (+60% with respect to Ctrl; p<0.05) and down regulated X-linked inhibitor of apoptosis protein. Apoptosis was blunted by Caspase-9 but not Caspase-8 inhibition. Uric acid induced changes in the mitochondrial membrane, elevations in reactive oxygen species and a pronounced up-regulation of NOX 4 mRNA and protein (p<0.05). In addition, both reactive oxygen species production and apoptosis was prevented by the NADPH oxidase inhibitor DPI as well as by Nox 4 knockdown. URAT 1 transport inhibition by probenecid and losartan and its knock down by specific siRNA, blunted apoptosis, suggesting a URAT 1 dependent cell death. In summary, our data show that uric acid increases the permissiveness of proximal tubule kidney cells to apoptosis by triggering a pathway involving NADPH oxidase signalling and URAT 1 transport. These results might explain the chronic tubulointerstitial damage observed in hyperuricaemic states and suggest that uric acid transport in tubular cells is necessary for urate-induced effects.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Adipokines are key mediators of inflammation in metabolic syndrome perpetuating the effect of excess nutrient intake by setting a self-maintaining vicious circle. Here, we assess levels of ...adiponectin and leptin in a cohort of individuals with MetS undergoing dietary and behavioral counselling. Specifically, we investigate their role as predictors of metabolic syndrome remission after 1 year.
Patients with MetS (n = 127) received behavioral and dietary recommendations and were followed-up for 1 year. Serum was available for 108 individuals, levels of adiponectin and leptin were tested at baseline, at 6 months (t1) and after 1 year (t2). Adiponectin/leptin (A/L) ratio was also calculated and tested for predictive ability.
At the end of the follow-up period, 59 patients did not show enough criteria to define MetS anymore. When considered alone, adiponectin and leptin levels did not show difference over follow-up. Their ratio instead was significantly reduced at t1 and t2 with respect to baseline. Remitters also showed lowers level of leptin and A/L ratio as compared to non-remitters at t1. At this timepoint, A/L ratio independently predicted MetS remission at 1 year OR 9.082 95%CI (1.394–59.160), p = 0.021. Bootstrap resampling analysis internally validated our findings.
Preliminary results from our pilot study suggest that MetS remission after counselling associates with changes in adipokine balance. A/L ratio decreases overtime and its value at 6 months can independently predict MetS remission.
•Adipokines are key mediators of inflammation in metabolic syndrome.•Adipokine balance change in individuals with metabolic syndrome after medical counselling.•Adiponectin/leptin ratio might predict metabolic syndrome remission.
Serum Uric Acid and Risk of CKD in Type 2 Diabetes De Cosmo, Salvatore; Viazzi, Francesca; Pacilli, Antonio ...
Clinical journal of the American Society of Nephrology,
11/2015, Letnik:
10, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Serum uric acid may predict the onset and progression of kidney disease, but it is unclear whether uric acid is an independent risk factor for diabetic nephropathy. Our aim was to study the ...relationship between uric acid levels and the development of CKD components in patients with type 2 diabetes.
Longitudinal study of a cohort of patients with type 2 diabetes from the database of the Italian Association of Clinical Diabetologists network. From a total of 62,830 patients attending the diabetes centers between January 1, 2004, and June 30, 2008, we considered those with baseline eGFR values ≥60 ml/min per 1.73 m2 and normal albumin excretion (n=20,142). Urinary albumin excretion, GFR, and serum uric acid were available in 13,964 patients. We assessed the association of serum uric acid quintiles with onset of CKD components by multinomial logistic regression model adjusting for potential confounders. We calculated the relative risk ratios (RRRs) for eGFR <60 ml/min per 1.73 m2, albuminuria, and their combination at 4 years.
At 4-year follow-up, 1109 (7.9%) patients developed GFR <60 ml/min per 1.73 m2 with normoalbuminuria, 1968 (14.1%) had albuminuria with eGFR ≥60 ml/min per 1.73 m2, and 286 (2.0%) had albuminuria with eGFR <60 ml/min per 1.73 m2. The incidence of eGFR <60 ml/min per 1.73 m2 increased in parallel with uric acid quintiles: Compared with the lowest quintile, RRRs were 1.46 (95% confidence interval CI, 1.14 to 1.88; P=0.003), 1.44 (95% CI, 1.11 to 1.87; P=0.006), 1.95 (95% CI, 1.48 to 2.58; P<0.001), and 2.61 (95% CI, 1.98 to 3.42; P<0.001) for second, third, fourth, and fifth quintiles, respectively. Serum uric acid was significantly associated with albuminuria only in presence of eGFR <60 ml/min per 1.73 m2.
Mild hyperuricemia is strongly associated with the risk of CKD in patients with type 2 diabetes.
Bempedoic acid (ETC-1002) is a first-in-class lipid-lowering agent recently approved by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for ...commercialization.
The aim was to assess, through a systematic review of the literature and a meta-analysis of the available phase 2 and phase 3 clinical studies, the effect of treatment with bempedoic acid on serum uric acid (SUA) concentration. Secondary outcomes were treatment-related variations in creatinine serum level and incidence of gout.
A systematic literature search in SCOPUS, PubMed Medline, ISI Web of Science and Google Scholar databases was conducted up to November 13th, 2019, in order to identify clinical trials potentially eligible for the meta-analysis. Effect sizes were expressed as absolute mean differences (MDs) and 95% confidence intervals (CIs).
Data were pooled from four clinical studies comprising ten arms, which included overall 3369 subjects, with 2213 in the active-treatment arm and 1156 in the control one. Meta-analysis of data suggested that treatment with bempedoic acid is related to a significant increase in SUA (MD 0.73, 95% CI 0.54-0.91, P < 0.001), serum creatinine (MD 0.04, 95% CI 0.03-0.05, P < 0.001) and the incidence of gout (odds ratio 3.56, 95% CI 1.24-10.19, P = 0.018). The relatively small number of subjects involved in the studies and the exclusion of patients with renal impairment from the clinical trials are important limitations of the meta-analysis. However, our data indicate potential safety issues with bempedoic acid and suggest that further studies are performed both to elucidate the pathogenetic mechanisms underlying these associations and to verify the long-term safety of this treatment.
Bempedoic acid seems to have unfavourable effects on SUA, creatinine level and the incidence of gout. The ongoing Cardiovascular Outcomes Trial (CVOT) will explore the longer-term safety of treatment with bempedoic acid and clarify its effect on cardiovascular events and mortality.
CRD42019146126.
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