Uric Acid Reduction Research Articles

Protective Effect of Trichosanthes Dioica Extract Against Gentamicin Induced Nephrotoxicity in Rats

Introduction: Nephropathy is one of the progressive complications prevailed all around the world that is observed which arises due to detrimental effects of metabolites created due to various metabolic and physiological reactions. Gentamicin is one of the drug that may cause nephrotoxicity. Objectives: Phytoremedies are being considered as to play deterrent role in the treatment of disease. T. dioica is widely distributed in Asian subcontinent and consumed as food. The present work is aimed to study nephroprotective activity of T. dioica. Subjects and Methods: Dried T. dioica fruits were extracted with methanol and the extract was subjected to phytochemical analysis. Acute toxicity was determined as per OECD guidelines. Gentamicin (80 mg/Kg) was used to induce nephrotoxicity. The extract was given orally. Kidney weight was determined and estimation of blood urea nitrogen, serum creatinine, uric acid, catalase, superoxide dismutase, glutathione peroxidase, lipid peroxidation, urinary electrolytes was performed. Results and Discussion: Decrement in serum urea and creatinine along with reduction in uric acid was observed. Similarly, restoration of antioxidant enzymes and normalization of urinary electrolytes and kidney weight was observed. Observations from present study divulged that T. dioica, which is a good source of antioxidant phytochemicals, is accountable for nephroprotective activity.

Reduction in Serum Uric Acid May Be Related to Methotrexate Efficacy in Early Rheumatoid Arthritis: Data from the Canadian Early Arthritis Cohort (CATCH).

OBJECTIVESThe mechanism of action of methotrexate in rheumatoid arthritis (RA) is complex. It may increase adenosine levels by blocking its conversion to uric acid (UA). This study was done to determine if methotrexate lowers UA in early RA (ERA).METHODSData were obtained from Canadian Early Arthritis Cohort, an incident ERA cohort. All ERA patients with serial UA measurements were included, comparing those with methotrexate use vs. no methotrexate exposure (controls). Analyses were exploratory. Patients with concomitant gout or taking UA-lowering therapies were excluded.RESULTSIn total, 49 of the 2,524 ERA patients were identified with data available for both pre-methotrexate UA levels and post-methotrexate UA levels (300 µmol/L and 273 µmol/L, respectively; P = 0.035). The control group not taking methotrexate had a mean baseline UA level of 280 µmol/L and a follow-up level of 282 µmol/L (P = 0.448); mean change in UA with methotrexate was −26.8 µmol/L vs. 2.3 µmol/L in the no methotrexate group (P = 0.042). Methotrexate users with a decrease in UA had a disease activity score of 2.37 for 28 joints when compared with the controls (3.26) at 18 months (P = 0.042). Methotrexate users with decreased UA had a lower swollen joint count (SJC) of 0.9 at 18 months, whereas methotrexate users without lowering of UA had an SJC of 4.5 (P = 0.035). Other analyses were not significant.CONCLUSIONSMethotrexate response is associated with lowering of serum UA in ERA compared to nonusers. This may be due to changes in adenosine levels. Methotrexate response is associated with lower UA and fewer swollen joints compared to nonresponders.

A Randomized Controlled Trial of the Effects of Febuxostat Therapy on Adipokines and Markers of Kidney Fibrosis in Asymptomatic Hyperuricemic Patients With Diabetic Nephropathy.

Background:In observational studies, higher uric acid levels are associated with metabolic syndrome, diabetes, and kidney disease.Objective:The objective of this study is to examine whether reduction of plasma uric acid with febuxostat, a xanthine oxido reductase inhibitor, impacts adipose tissue oxidative stress, adipokines, and markers of systemic inflammation or kidney fibrosis.Design:This was a double-blinded randomized controlled trial.Setting:Academic university setting was used.Patients:Overweight or obese adults with hyperuricemia and type 2 diabetic nephropathy were included.Measurements:Adipose tissue thiobarbituric acid reducing substances (TBARS) and adiponectin concentrations and urinary transforming growth factor–β (TGF-β) were primary endpoints. Plasma C-reactive protein, high molecular weight–adiponectin, interleukin–6, tumor necrosis factor–α, and TBARS and albuminuria were among predefined secondary endpoints.Methods:Participants were randomly assigned to febuxostat (n = 40) or matching placebo (n = 40) and followed for 24 weeks.Results:Baseline plasma uric acid levels were 426 ± 83 µmol/L; 95% completed the study. Estimated glomerular filtration rate (eGFR) declined from 54 ± 17 mL/min/1.73 m2 at baseline to 51 ± 17 mL/min/1.73 m2 at 24 weeks (P = .05). In separate mixed-effects models, compared with placebo, febuxostat reduced uric acid by 50% (P < .001) but had no significant effects on subcutaneous adipose tissue TBARS (−7.4%, 95% confidence interval [CI], 57.4%-101.4%) or adiponectin (6.7%, 95% CI, 26.0%-53.8%) levels or urinary TGF-β/creatinine ratio (18.0%, 95% CI, 10.0%-54.8%) or secondary endpoints.Limitations:Relatively modest sample size and short duration of follow-up.Conclusions:In this population with progressive diabetic nephropathy, febuxostat effectively reduced plasma uric acid. However, no detectable effects were observed for the prespecified primary or secondary endpoints.Trial Registration:The study was registered in clinicaltrials.gov (NCT01350388).

Comparison of the Renoprotective Effect of Febuxostat for the Treatment of Hyperuricemia between Patients with and without Type 2 Diabetes Mellitus: A Retrospective Observational Study.

Objective The effects of febuxostat therapy on hyperuricemia in patients with and without type 2 diabetes were compared in this retrospective observational study after pair-matching using the propensity scores. Methods In total, 160 patients with hyperuricemia were studied as the treated set, and the 155 subjects in whom the administration of febuxostat was not discontinued during the observation period were investigated in the full analysis. The study subjects were divided into two groups based on the style of initiation of febuxostat: initial and switching therapy from allopurinol administration. Results The reduction in the serum uric acid (sUA) levels at six months after the initiation of febuxostat administration did not significantly differ between the patients with and without diabetes in both the initial (206±114 and 226±113 μmol/L in patients with and without diabetes, respectively) and switching (154±91 and 129±90 μmol/L in patients with and without diabetes, respectively) therapy groups. The eGFR values were significantly increased compared to the baseline levels only in the patients without diabetes. The changes in the eGFR values were significantly associated with the presence of diabetes and sUA at baseline in a multivariate analysis. The frequency of adverse events was not significantly different between the patients with and without diabetes. Conclusion Although febuxostat exerted a similar sUA-lowering effect against hyperuricemia in patients with type 2 diabetes compared to those without, the renoprotective effect was attenuated in those with diabetes compared to nondiabetic subjects.

Antiurolithiatic effect of lithocare against ethylene glycol-induced urolithiasis in Wistar rats.

Aim:This study is aimed to investigate the protective effect of Lithocare (LC) (a polyherbal formulation) against ethylene glycol (EG) induced urolithiasis in Wistar rats.Materials and Methods:The protective effect of LC (400 and 800 mg/kg) was evaluated using EG-induced urolithiasis in rats.Results:Administration of EG in drinking water resulted in hyperoxaluria, hypocalcemia as well as an increased renal excretion of phosphate. Supplementation with LC significantly reduced the urinary calcium, oxalate, and phosphate excretion dose-dependently. There was a significant reduction in the levels of calcium, oxalate as well as a number of calcium oxalate crystals deposits in the kidney tissue of rats administered with LC in EG-treated rats. There was a significant reduction in creatinine, urea, uric acid, and blood urea nitrogen when LC was administered in EG-treated rats.Conclusions:From this study, it was concluded that the supplementation of LC protected EG-induced urolithiasis as it reduced the growth of urinary stones. The mechanism underlying this effect might be due to its antioxidant, diuretic, and reduction in stone-forming constituents.

A Comparison of Single Dose Rasburicase 3 Mg Versus 6 Mg for the Management of Tumor Lysis Syndrome

Introduction: Rasburicase, a recombinant form of urate oxidase, is a highly effective treatment for tumor lysis syndrome (TLS). Although the FDA-approved dose for rasburicase is 0.2 mg/kg/day for up to five days, many centers have adopted alternative dosing strategies to decrease cost, the most common being a single 6 mg dose. We hypothesized that further reducing the dose to 3 mg would result in similar efficacy and yield significant cost savings compared to the 6 mg dose strategy.Methods: We conducted a retrospective cohort study to examine the comparative effectiveness of a single 3 mg dose of rasburicase versus a single 6 mg dose in 108 adults with hematological malignancies presenting with a baseline uric acid (UA) ≤ 12 mg/dL between June 2009 and February 2015. Prior to January 2012, our institutional policy recommended a single 6 mg dose for all patients who met criteria for rasburicase for TLS. In January 2012, the policy was amended to recommend a single 3 mg dose for patients with a baseline UA ≤ 12 mg/dL. Thus, the study included 56 patients with UA ≤ 12 who received a single 6 mg dose prior to the policy modification and 52 patients with UA ≤ 12 given the 3 mg dose after the amendment. The primary endpoint was the percentage of patients who achieved a UA ≤ 8 mg/dL (the upper limit of normal at our institution) 24 hours after a single dose of rasburicase. Fisher's exact test was used to analyze categorical variables and t-tests were used to analyze continuous variables. The a priori level of significance was set at α < 0.05.Results: The mean baseline UA was 9.3 mg/dL and 9.8 mg/dL in the 3 mg arm and 6 mg arm, respectively (P = .19). At 24 hours there was no difference in the percentage of patients who achieved a UA ≤ 8 mg/dL (92% vs. 98%; P = 0.36). In addition, there was no difference in the percentage of patients who achieved a UA ≤ 8 mg/dL at 48 hours (98% vs. 100%; P = 0.48). Six (11.5%) patients in the 3 mg arm and one (1.8%) patient in the 6 mg arm required a second dose of rasburicase to achieve a UA <8 mg/dL (P = 0.1). Of note, the 6 mg group had a greater percent reduction in UA from baseline compared to the 3 mg group at both 24 hours (-68.1% vs. -48.6%; P < .01) and 48 hours (-69.3% vs. -51.3%; P = 0.02) after rasburicase administration. There was no difference in the percent change of serum creatinine between the two dosing strategies at 24 hours (-6.5% vs. 0.1%; P = 0.11) or 48 hours (-4.5% vs. -2.5%; P = 0.22). In addition, no difference was observed with respect to the percent of patients who required renal replacement therapy within 7 days of rasburicase administration (8.9% vs. 9.6% P = 1.0). Based on the average wholesale price of $815 for one 1.5 mg vial of rasburicase, the single 3 mg dose was associated with approximately $1,500 cost savings per encounter compared to the 6 mg dose.Conclusion: A single 3 mg dose of rasburicase was as effective as 6 mg in normalizing UA within 24 hours. Our findings demonstrate that administering a single 3 mg dose of rasburicase is a cost-effective alternative for TLS management in patients with hematological malignancies presenting with a UA ≤ 12 mg/dL. DisclosuresSvoboda:Immunomedics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding. Ganetsky:Onyx: Speakers Bureau.

Flavonoids and phenylethanoid glycosides from Lippia nodiflora as promising antihyperuricemic agents and elucidation of their mechanism of action

Ethnopharmacological relevanceLippia nodiflora has been traditionally used in the Ayurvedic, Unani, and Sidha systems, as well as Traditional Chinese Medicine (TCM) for the treatment of knee joint pain, lithiasis, diuresis, urinary disorder and swelling. Aim of the studyThe present study aims to investigate the antihyperuricemic effect of the L. nodiflora methanol extract, fractions, and chemical constituents and their mechanism of action in the rat model. Materials and methodsThe mechanisms were investigated by performing xanthine oxidase inhibitory, uricosuric, and liver xanthine oxidase/xanthine dehydrogenase (XOD/XDH) inhibitory studies in potassium oxonate- and hypoxanthine-induced hyperuricemic rats. The plant safety profile was determined using acute toxicity study. The molecular docking of the active compound to the xanthine oxidase was simulated using computer aided molecular modeling analysis. ResultsOral administration of methanol extract showed a dose-dependent reduction effect on the serum uric acid level of hyperuricemic rats. F3 was the most potent fraction in lowering the serum uric acid level of hyperuricemic rats. Bioactivity-guided purification of F3 afforded two phenylethanoid glycosides, arenarioside (1) and verbascoside (2) and three flavonoids, 6-hydroxyluteolin (3), 6-hydroxyluteolin-7-O-glycoside (4), and nodifloretin (5). The highest serum uric acid reduction effect was exhibited by 3 (66.94%) in hyperuricemic rats, followed by 5 (55.97%), 4 (49.16%), 2 (29.03%), and 1 (22.08%) at 0.2mmol/kg. Dose-response investigation on 3 at doses of 0.05, 0.1, and 0.3mmol/kg produced a significant dose-dependent reduction on the serum uric acid level of hyperuricemic rats. Repeated administration of F3 or 3 to the hyperuricemic rats for 10 continuous days resulted in a significant and progressive serum uric acid lowering effect in hyperuricemic rats. In contrast, methanol extract and F3 did not reduce serum uric acid level of normoruricemic rats. In addition, F4 significantly increased the uric acid excretion of hyperuricemic rats at 200mg/kg. No toxic effect was observed in rats administered with 5000mg/kg of methanol extract or F3. ConclusionThe potential application of L. nodiflora against hyperuricemia in the animal in accordance with its traditional uses has been demonstrated in the present study for the first time. The antihyperuricemic effect possessed by L. nodiflora was contributed mainly by liver XOD/XDH inhibitory activities and partially by uricosuric effect. Flavonoids mainly accountable for the uric acid lowering effect of L. nodiflora through the inhibition of XOD/XDH activities.

Evaluation of antigout activity of Phyllanthus emblica fruit extracts on potassium oxonate-induced gout rat model.

Aim:The present study has been conducted to evaluate antigout activity of aqueous and alcoholic extracts of Phyllanthus emblica fruits following its 28 days repeated oral administration on potassium oxonate-induced gout rat model.Materials and Methods:The study was conducted on 42 male Sprague-Dawely rats dividing them in seven groups having six rats in each group. Groups I, II, and III served as vehicle control group, gout control group, and standard treatment control group, respectively. Rats of all the groups except vehicle control group were administered potassium oxonate at 250 mg/kg (IP), throughout the study period (28 days) for induction of gout. Groups IV and V received aqueous extract of P. emblica at 200 and 400 mg/kg, and Groups VI and VII received alcoholic extract of P. emblica at 200 and 400 mg/kg (daily oral for 28 days). At the end of study, all the rats were subjected to blood collection; blood and serum sample were analyzed for hematological and biochemical parameters, respectively. After collection of blood samples on the 29th day, all the rats were sacrificed and subjected to post mortem examination to determine the presence or absence of gross and histopathological lesions in kidney tissues.Results:At the end of study, rats of gout control group showed increase in platelets counts, serum creatinine, uric acid, blood urea nitrogen (BUN), and xanthine oxidase (XO) enzyme level along with alterations in kidney tissues as compared to vehicle control group. Gouty rats treated with aqueous and alcoholic extracts of P. emblica at 200 and 400 mg/kg body weight and standard treatment allopurinol at 5 mg/kg body weight showed reduction in platelets counts, serum creatinine, uric acid, BUN, and XO enzyme level along with significant improvements in histological structure of kidney as compared to rats of gout control group.Conclusion:Oral administration of aqueous and alcoholic extracts of P. emblica fruits for 28 days has shown protection against gout in dose-dependent manner in rats.

A J-Shaped Association Between Serum Uric Acid Level and Allograft Outcomes After Living Donor Kidney Transplantation.

Hyperuricemia following kidney transplantation (KT) may contribute to a decline in allograft renal function, but be affected by KT-related confounding factors. Some studies have even suggested that a reduction in serum uric acid (UA) is associated with poor patient outcomes. Thus, we retrospectively analyzed the impact of serum UA on allograft outcomes in 281 KT recipients. KT recipients were divided into five groups according to serum UA level (mg/dL): Group I (n = 46), ≤ 5; Group II (n = 62), > 5 and ≤ 6; Group III (n = 70), > 6 and ≤ 7; Group IV (n = 53), > 7 and ≤ 8; Group V (n = 50), > 8. Regression analysis showed that serum UA level was significantly associated with future allograft function. In a Kaplan-Meier analysis, the dialysis-free survival of Group II recipients was better than that of the other groups (Group I, 140 ± 5 months; Group II, 208 ± 7 months; Group III, 148 ± 4 months; Group IV, 185 ± 12 months; Group V, 164 ± 11 months; P = 0.0164). In Cox proportional hazard models adjusting for estimated glomerular filtration rate, the relative risk of allograft loss still tended to be elevated in Group I (HR=3.417, 95% CI 1.138-10.258) and Group V (HR=2.793, 95% CI 1.108-7.041), using Group II as the reference. Our results suggest that there is a J-shaped association between serum UA levels and allograft outcomes in living donor KT recipients.

Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis.

BackgroundHyperuricemia may contribute to renal injury. We do not know whether use of treatments that lower urate reduce the progression of chronic kidney disease (CKD) and cardiovascular disease. We performed a systematic review and meta-analysis of randomized controlled trials to assess the benefits and risks of treatments that lower urate in patients with stages 3-5 CKD.MethodsWe searched MEDLINE, EMBASE, CENTRAL, Web of Science and trial registers for randomized controlled trials (RCTs) without language restriction. Two authors independently screened articles, assessed risk of bias and extracted data. Data obtained included serum uric acid, serum creatinine or other estimates of glomerular filtration rate, incidence of end-stage renal disease (ESRD), systolic and diastolic blood pressure, proteinuria, cardiovascular disease and adverse events.ResultsFrom the 5497 citations screened, 19 RCTs enrolling 992 participants met our inclusion criteria. Given significant heterogeneity in duration of follow-up and study comparators, only trials greater than 3 months comparing allopurinol and inactive control were meta-analyzed using random effects models. Pooled estimate for eGFR was in favour of allopurinol with a mean difference (MD) of 3.2 ml/min/1.73 m2, 95% CI 0.16-6.2 ml/min/1.73 m2, p = 0.039 and this was consistent with results for serum creatinine. Statistically significant reductions in serum uric acid, systolic and diastolic blood pressure were found, favouring allopurinol. There were insufficient data on adverse events, incidence of ESRD and cardiovascular disease for analysis.ConclusionsAdequately powered RCTs are needed to establish whether treatments that lower urate have beneficial renal and cardiovascular effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-015-0047-z) contains supplementary material, which is available to authorized users.

Diabetic nephropathy: current diagnostics and treatment

Diabetic kidney disease is a leading cause of renal failure in Germany. Albuminuria is an early diagnostic indicator of renal damage in diabetes and, aside from renal failure, a major risk factor of cardiovascular disease. An early diagnosis of diabetic kidney disease is of great importance to reduce associated cardiovascular mortality; glycemic control should aim for HbA1c levels of < 7 %. Guidelines on blood pressure differ, but it should generally be reduced to < 140/90mmHg; stricter limits should be applied if albuminuria is present. ACE inhibitors (ACE-I) or angiotensin receptor blockers (ARB) should be preferred for blood pressure control. A combination of ACE-Is and ARBs or a renin-inhibitor therapy does not improve cardiovascular outcome, instead it increases the rate of adverse events, e.g., hyperkalemia or renal failure. Lipid control, usually with statins, should be started at an early phase of renal failure. VitaminD receptor activation and uric acid reduction might play a future role in the treatment of diabetic kidney disease. Pharmacological modification of inflammatory signaling appears to be promising but is not yet of clinical relevance.

The molecular insight into the antihyperuricemic and renoprotective effect of Shuang Qi gout capsule in mice

Ethnopharmacological relevanceShuang-Qi gout capsule, a traditional Chinese medicine prescription, has been used in the treatment of, gout arthritis, arthralgia and inflammation. Since renal urate overload associated with severe disability including gout, elimination of excess renal uric acid is highly essential. Therefore, in this study we evaluated the antihyperuricemic and the renoprotective effect of the Shuang Qi gout capsule (SQ) with elucidation of its mechanism. Materials and methodsWe assessed the antihyperuricemic activity of SQ on urinary and serum uric acid, creatinine, blood urea nitrogen, fractional excretion of uric acid (FEUA) and glomerular filtration rate of creatinine and uric acid in potassium oxonate (PO) – induced mice as well as in non-induced mice. To illuminate the mechanism of antihyperuricemic activity, we investigated renal transport activity and the expression of mRNA levels in PO-induced and non-induced mice by western blot and RT-PCR methods. ResultsSQ showed significant reduction in serum uric acid, creatinine and blood urea nitrogen levels and marked elevation of urine uric acid, creatinine and FEUA levels only in hyperuricemic mice. Furthermore, SQ could recover the altered expressions of proteins and mRNA levels of all the main renal transporters significantly in dose dependent manner. ConclusionsSQ could effectively regulate the main renal transporters denoted its denote probable antihyperuricemic mechanism of SQ and its dose dependent uricosuric effect. In addition, SQ attenuated the deleterious effects of hyperuricemia with renal dysfunction. Thus SQ could be a potent antihyperuricemic agent which can perform as a safer and effective agent in the management of hyperuricemia via regulating the renal transporters.

Resposta renal à maltodextrina e ao treinamento em diferentes intensidades

The objective was to investigate the renal response to ingestion of maltodextrin and aerobic or anaerobic training in rats. Materials and methodsThe protocol consisted of 8 weeks of swimming aerobic (5% overload) or anaerobic (10% overload). During 37 days, the animals were supplemented by gavage with a daily dose of 0.48g.Kg−1 maltodextrin dissolved in water or with pure water, before training. ResultsThe anaerobic training caused increases in concentrations of uric acid, creatinine and total protein and reduction in renal glycogen in kidney. The maltodextrin caused an increase in renal glycogen. ConclusionMaltodextrin and anaerobic training provided changes in parameters of renal function in response of this organ to these external stimuli.

Uric acid promotes left ventricular diastolic dysfunction in mice fed a Western diet.

The rising obesity rates parallel increased consumption of a Western diet, high in fat and fructose, which is associated with increased uric acid. Population-based data support that elevated serum uric acids are associated with left ventricular hypertrophy and diastolic dysfunction. However, the mechanism by which excess uric acid promotes these maladaptive cardiac effects has not been explored. In assessing the role of Western diet-induced increases in uric acid, we hypothesized that reductions in uric acid would prevent Western diet-induced development of cardiomyocyte hypertrophy, cardiac stiffness, and impaired diastolic relaxation by reducing growth and profibrotic signaling pathways. Four-weeks-old C57BL6/J male mice were fed excess fat (46%) and fructose (17.5%) with or without allopurinol (125 mg/L), a xanthine oxidase inhibitor, for 16 weeks. The Western diet-induced increases in serum uric acid along with increases in cardiac tissue xanthine oxidase activity temporally related to increases in body weight, fat mass, and insulin resistance without changes in blood pressure. The Western diet induced cardiomyocte hypertrophy, myocardial oxidative stress, interstitial fibrosis, and impaired diastolic relaxation. Further, the Western diet enhanced activation of the S6 kinase-1 growth pathway and the profibrotic transforming growth factor-β1/Smad2/3 signaling pathway and macrophage proinflammatory polarization. All results improved with allopurinol treatment, which lowered cardiac xanthine oxidase as well as serum uric acid levels. These findings support the notion that increased production of uric acid with intake of a Western diet promotes cardiomyocyte hypertrophy, inflammation, and oxidative stress that lead to myocardial fibrosis and associated impaired diastolic relaxation.

Abstract 13640: Dapagliflozin Lowers HbA1c, Systolic Blood Pressure and Serum Uric Acid in Patients With Type 2 Diabetes and Hypertension, Regardless of Class of Concomitant Antihypertensive Therapy

Hypertension (HTN) in Type 2 diabetes (T2D) is often treated with an ACEi/ARB + additional antihypertensives agents (AHTs). Dapagliflozin (DAPA) is an inhibitor of sodium glucose co-transporter 2, reducing hyperglycemia in T2D by increasing urinary glucose excretion. This is associated with weight reduction, osmotic diuresis and serum uric acid reduction, all of which may contribute to BP lowering. This Phase 3 study assessed 12 weeks of DAPA 10 mg (N=225) or placebo (PBO; N=224) in T2D patients (HbA1c 7.0-10.5%) with HTN (seated SBP / DBP 140 - &lt;165 / 85 - &lt;105 mmHg) receiving glucose-lowering drugs, an ACEi/ARB, + an additional AHT: β-blockers (27%), Ca-channel blockers (CCBs; 27%), thiazide/thiazide-like diuretics (diuretics; 44%) or α-adrenergic antagonists (α-AAs; 1%). Main results were presented previously. Here we describe treatment effects according to the additional AHT (α-AA group not analyzed due to small sample size). Patients were randomized to DAPA 10 mg or PBO, stratified by insulin use and diuretics vs CCBs/β-blockers/α-AA. Baseline characteristics were similar for DAPA vs PBO. Reduction in HbA1c and mean 24-hour ambulatory SBP was greater with DAPA vs PBO overall, and appeared greater with DAPA vs PBO in all AHT sub-groups (Fig). Reduction in seated SBP was greater with DAPA overall (diff vs PBO; –4.28 [95% CI: –6.54, –2.02] mmHg) and also appeared greater with DAPA in sub-groups (diff vs PBO: β-blockers –5.76 [–10.28, –1.23]; CCB –5.13 [–9.47, –0.79]; diuretics –2.38 [–6.16, 1.40] mmHg). Serum uric acid decreased more with DAPA overall (diff vs PBO; –0.40 [95% CI: –0.57, –0.23]), and was observed to decrease more with DAPA in sub-groups (diff vs PBO: β-blockers –0.62 [–0.95, –0.29]; CCBs –0.33 [–0.65, –0.01]; diuretics –0.22 [–0.49, 0.05] mg/dL). DAPA was well tolerated; AEs were similar for DAPA (44%) vs PBO (42%). In summary, regardless of the concomitant AHT, DAPA reduced HbA1c, SBP and serum uric acid vs PBO in patients with uncontrolled T2D and HTN.

Sodium–glucose linked transporter-2 inhibitors: potential for renoprotection beyond blood glucose lowering?

The proximal tubule's sodium-glucose linked transporter-2 (SGLT2) accounts for the vast majority of glucose reabsorption by the kidney. Its selective inhibition, accordingly, leads to substantial glycosuria, lowering blood glucose, and facilitating weight loss in individuals with diabetes. During the past year, two SGLT2 inhibitors, canagliflozin and dapagliflozin, have been approved for the treatment of type 2 diabetes. Beyond their anti-hyperglycemic properties, however, this new class of drugs has several other attributes that provide a theoretical basis for kidney protection. Like agents that block the renin-angiotensin system, SGLT2 inhibitors also reduce single-nephron glomerular filtration rate (SNGFR) in the chronically diseased kidney, though by quite different mechanisms. Additional potentially beneficial effects of SGLT2 inhibition include modest reductions in blood pressure and plasma uric acid. Finally, cell culture studies indicate that glucose uptake from the tubular lumen, as well as from the basolateral compartment, can contribute to proximal tubular production of extracellular matrix proteins. Whether such attributes will translate into reducing the progression of chronic kidney disease will require the undertaking of long-term, dedicated studies.

Abstract 608: Uric Acid Potentially Interacts With Parathyroid Hormone To Promote Left Ventricular Diastolic Dysfunction In Mice Fed A Western Diet

Hyperuricemia is frequently observed in obese people and rising obesity rates parallel increased consumption of a high-fat/high-fructose western diet (WD). Epidemiologic and clinical data suggest that serum uric acid (UA) is positively associated with serum parathyroid hormone (PTH) and may be linked with left ventricular (LV) hypertrophy and LV diastolic dysfunction. Accordingly, we hypothesized that allopurinol, a potent xanthine oxidase (XO) inhibitor, would prevent development of LV diastolic dysfunction, independent of blood pressure, by reducing the levels of UA and PTH. Four week-old C57BL6/J male mice were fed a WD and water with 125mg/L allopurinol. After 16 weeks, we assessed levels of UA, XO activity, PTH, as well as diastolic function by cardiac MRI and cardiac ultrastructure by transmission electron microscopy (TEM). Body weight and fat composition were obtained along with HOMA -IR testing for insulin resistance. Allopurinol has been show to exert no effect on blood pressure. High resolution cardiac MRI revealed diastolic dysfunction with WD feeding that was prevented by allopurinol (LV diastolic relaxation time 35.3 ms for WD, 25.4 ms for CD and 27.7 ms for WD+ allopurinol, p value &lt;0.01; Initial filling rate 0. 28 μl/ms for WD, 0.43 μl/ms for CD and 0.42 μl/ms for WD+ allopurinol, p value &lt;0.05). Body weight, fat mass, and HOMA-IR were increased by WD feeding but not significantly improved by allopurinol. However, allopurinol markedly decreased the WD-induced increase in heart weight associated with activation of translational S6 kinase. TEM examination of myocardial ultrastructure revealed that WD induced remodeling changes with large mitochondria with disordered cristae and increased lysosomes. The ultrastructural changes were improved with treatment by allopurinol. Furthermore, allopurinol significantly inhibited both of plasma and urine UA levels and cardiac XO activity caused by WD. Interestingly , WD increased PTH levels which were decreased in parallel with reductions in uric acid with allopurinol. These findings support the notion that increased plasma levels of UA, in concert with elevated PTH, may play a key role in LV hypertrophy and associated LV diastolic dysfunction that result from consuming a WD high in fructose and fat.

Effects of green tea extract on serum uric acid and urate clearance in healthy individuals.

The objective of this study was to investigate the hypouricemic effects of green tea extract (GTE) in healthy individuals. This study comprised 1-week control, 2-week interventional, and 1-week follow-up periods. Participants were assigned randomly at the interventional period to consume GTE at 2 (GTE2), 4 (GTE4), or 6 (GTE6) g/d. Levels of serum uric acid (SUA), uric acid clearance, and serum antioxidant power (using trolox equivalent antioxidant capacity assay) were measured at both ends of each study period. Of 30 participants, 11, 11, and 8 received GTE2, GTE4, and GTE6, respectively. After 2 weeks of consumption, the mean SUA level tended to decrease in all groups, with no statistical significance. Serum uric acid reduction was greatest in GTE2 (from 4.81 ± 0.81 mg/dL to 4.64 ± 0.92 mg/dL, 3.53%). Uric acid clearance decreased significantly in GTE2 (from 11.37 ± 6.41 mL/min per 1.73 m to 7.44 ± 2.74 mL/min per 1.73 m, 34.56%, P < 0.05) and GTE4 (from 8.36 ± 3.41 mL/min per 1.73 m to 5.78 ± 2.33 mL/min per 1.73 m, 30.86%, P < 0.05). Serum antioxidant capacity (TEAC) increased significantly in GTE6 (from 32.77 ± 3.39 mg/mL to 35.41 ± 3.17 mg/mL, 8.06%, P < 0.05). There was no significant change in creatinine clearance. Gastrointestinal adverse events were common, but usually mild, with no medical treatment required. Green tea extract may modestly lower SUA level and decreases uric acid clearance. Green tea extract also significantly elevated serum antioxidant capacity with a positive dosage effect. The effect of GTE on SUA in healthy individuals was short term. The effects of GTE on urate handling in patients with hyperuricemia or gout need to be determined.

Recombinant Lactobacillus plantarum expressing and secreting heterologous oxalate decarboxylase prevents renal calcium oxalate stone deposition in experimental rats.

BackgroundCalcium oxalate (CaOx) is the major constituent of about 75% of all urinary stone and the secondary hyperoxaluria is a primary risk factor. Current treatment options for the patients with hyperoxaluria and CaOx stone diseases are limited. Oxalate degrading bacteria might have beneficial effects on urinary oxalate excretion resulting from decreased intestinal oxalate concentration and absorption. Thus, the aim of the present study is to examine the in vivo oxalate degrading ability of genetically engineered Lactobacillus plantarum (L. plantarum) that constitutively expressing and secreting heterologous oxalate decarboxylase (OxdC) for prevention of CaOx stone formation in rats. The recombinants strain of L. plantarum that constitutively secreting (WCFS1OxdC) and non-secreting (NC8OxdC) OxdC has been developed by using expression vector pSIP401. The in vivo oxalate degradation ability for this recombinants strain was carried out in a male wistar albino rats. The group I control; groups II, III, IV and V rats were fed with 5% potassium oxalate diet and 14th day onwards group II, III, IV and V were received esophageal gavage of L. plantarum WCFS1, WCFS1OxdC and NC8OxdC respectively for 2-week period. The urinary and serum biochemistry and histopathology of the kidney were carried out. The experimental data were analyzed using one-way ANOVA followed by Duncan’s multiple-range test.ResultsRecombinants L. plantarum constitutively express and secretes the functional OxdC and could degrade the oxalate up to 70–77% under in vitro. The recombinant bacterial treated rats in groups IV and V showed significant reduction of urinary oxalate, calcium, uric acid, creatinine and serum uric acid, BUN/creatinine ratio compared to group II and III rats (P < 0.05). Oxalate levels in kidney homogenate of groups IV and V were showed significant reduction than group II and III rats (P < 0.05). Microscopic observations revealed a high score (4+) of CaOx crystal in kidneys of groups II and III, whereas no crystal in group IV and a lower score (1+) in group V.ConclusionThe present results indicate that artificial colonization of recombinant strain, WCFS1OxdC and NC8OxdC, capable of reduce urinary oxalate excretion and CaOx crystal deposition by increased intestinal oxalate degradation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-014-0086-y) contains supplementary material, which is available to authorized users.

Allopurinol initiation and change in blood pressure in older adults with hypertension.

Hypertension is a key risk factor for cardiovascular disease, and new treatments are needed. Uric acid reduction lowers blood pressure (BP) in adolescents, suggesting a direct pathophysiological role in the development of hypertension. Whether the same relationship is present in older adults is unknown. We explored change in BP after allopurinol initiation using data from the UK Clinical Practice Research Datalink. Data were extracted for patients with hypertension aged >65 years who were prescribed allopurinol with pretreatment and during treatment BP readings. Data from comparable controls were extracted. The change in BP in patients with stable BP medication was the primary outcome and was compared between groups. Regression analysis was used to adjust for potential confounding factors, and a propensity-matched sample was generated. Three hundred sixty-five patients who received allopurinol and 6678 controls were included. BP fell in the allopurinol group compared with controls (between-group difference in systolic and diastolic BP: 2.1 mm Hg; 95% confidence interval, -0.6 to 4.8; and 1.7 mm Hg; 95% confidence interval, 0.4-3.1, respectively). Allopurinol use was independently associated with a fall in both systolic and diastolic BP on regression analysis (P<0.001). Results were consistent in the propensity-matched sample. There was a trend toward greater fall in BP in the high-dose allopurinol group, but change in BP was not related to baseline uric acid level. Allopurinol use is associated with a small fall in BP in adults. Further studies of the effect of high-dose allopurinol in adults with hypertension are needed.