Increase In Serum Urate Research Articles

Serum Urate and Risk of Chronic Kidney Disease: A Mendelian Randomization Study Using Taiwan Biobank

ObjectiveTo evaluate the association between serum urate and risk of incident chronic kidney disease (CKD) and to assess whether serum urate plays a causal role in CKD. Patients and MethodsWe conducted a prospective cohort study and Mendelian randomization analysis that analyzed longitudinal data from the Taiwan Biobank between January 1, 2012, and December 31, 2021. ResultsA total of 34,831 individuals met the inclusion criteria, of which 4697 (13.5%) had hyperuricemia. After a median (interquartile range) follow-up of 4.1 (3.1-4.9) years, 429 participants developed CKD. After adjustment for age, sex, and comorbid conditions, each mg/dL increase in serum urate was associated with a 15% higher risk of incident CKD (HR, 1.15; 95% CI, 1.08 to 1.24; P<.001). The genetic risk score and seven Mendelian randomization methods revealed no significant association between serum urate levels and the risk of incident CKD (HR, 1.03; 95% CI, 0.72 to 1.46; P=0.89; all P>.05 for 7 Mendelian randomization methods). ConclusionThis prospective, population-based cohort study showed that elevated serum urate is a significant risk factor for incident CKD; however, Mendelian randomization analyses failed to provide evidence that serum urate had a causal effect on CKD in the East Asian population.

Not all the eggs and the chickens are the same: The case of uric acid and metabolic syndrome

Uric acid represents the end-product of purine metabolism in humans and the great apes where it has played some evolutive roles over the time [ [1] Bardin T. Richette P. Definition of hyperuricemia and gouty conditions. Curr Opin Rheumatol. 2014; 26: 186-191 Crossref PubMed Scopus (218) Google Scholar ]. The production of uric acid is largely regulated by xanthine oxidoreductase (XOR) that is converting hypoxanthine to uric acid and is partially responsible for the increase in the serum levels of urate and its possible biological and pathological effects [ [1] Bardin T. Richette P. Definition of hyperuricemia and gouty conditions. Curr Opin Rheumatol. 2014; 26: 186-191 Crossref PubMed Scopus (218) Google Scholar ]. Historically the increase in serum urate has been linked to some dietary habits (e.g. alcohol, red meat, seafood, etc.) that however explain only a minor proportion of the variance in serum uric acid levels when compared with inherited genetic variants [ [2] Choi H._.K. Atkinson K. Karlson E.W. Willett W. Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med. 2004; 350: 1093-1103 Crossref PubMed Scopus (761) Google Scholar ]. More importantly, uric acid is also synthesized in the liver, intestines, muscle, and vascular endothelium and this endogenous production could be more strictly related to the effects of increased serum urate beyond its crystal precipitation at the level of joints, soft tissue, kidneys, and other organs [ [3] El Ridi R. Tallima H. Physiological functions and pathogenic potential of uric acid: a review. J Adv Res. 2017; 8: 487-493 Crossref PubMed Scopus (167) Google Scholar ]. Accumulating evidence has demonstrated the role of increased serum urate as a possible etiologic mechanism in the pathogenesis of cardiovascular, metabolic, and renal diseases [ 4 Borghi C. Agabiti-Rosei E. Johnson R.J. Kielstein J.T. Lurbe E. Mancia G. Redon J. Stack A.G. Tsioufis K.P. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease. Eur J Intern Med. 2020; 80: 1-11 Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar , 5 Borghi C. Agabiti-Rosei E. Johnson R.J. Kielstein J.T. Lurbe E. Mancia G. Redon J. Stack A.G. Tsioufis K.P. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease. Eur J Intern Med. 2020; 80: 1-11 Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar , 6 Borghi C. Agnoletti D. Cicero A.F.G. Lurbe E. Virdis A. Uric acid and hypertension: a review of evidence and future perspectives for the management of cardiovascular risk. Hypertension. 2022 Jun 6; (101161HYPERTENSIONAHA12217956) Crossref PubMed Google Scholar ]. In particular, the presence of hyperuricemia above the levels of 5.5 mg/dL has been reported as a risk factors for hypertension, atrial fibrillation (AF), chronic kidney disease (CKD), heart failure (HF), coronary artery disease (CAD), and cardiovascular death [ [4] Borghi C. Agabiti-Rosei E. Johnson R.J. Kielstein J.T. Lurbe E. Mancia G. Redon J. Stack A.G. Tsioufis K.P. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease. Eur J Intern Med. 2020; 80: 1-11 Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar , [5] Borghi C. Agabiti-Rosei E. Johnson R.J. Kielstein J.T. Lurbe E. Mancia G. Redon J. Stack A.G. Tsioufis K.P. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease. Eur J Intern Med. 2020; 80: 1-11 Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar ]. In addition, elevated levels of serum uric acid have been reported to increase the relative risk of diabetes and metabolic syndrome acting though an interference with insulin sensitivity that has been reported as significantly reduced in presence of increased serum urate before the development of hyperglycemia and correlated risk factors [ [7] Han T. Lan L. Qu R. Xu Q. Jiang R. Na L. Sun C Temporal relationship between hyperuricemia and insulin resistance and its impact on future risk of hypertension. Hypertension. 2017; 70 (Oct): 703-711 Crossref PubMed Scopus (43) Google Scholar ]. This observations and many others in the same direction have supported the idea that uric acid per se or the mechanism of its production can be involved in the progressive reduction in tissue insulin sensitivity that may explain the progression toward metabolic abnormalities, increased blood pressure and atherogenic dyslipidemia that can largely contribute to the excess in the risk of cardiovascular disease observed in patients with elevated serum urate levels.

Renal Transcriptional Profiles of Hyperuricemic Mouse Models Reveal Urate Dependent Alternations in Metabolic Pathways

Increased serum urate (hyperuricemia, HUA) contributes to the development of kidney stones, chronic kidney disease, cardiovascular disease, metabolic syndrome, and gout. HUA is caused by an underexcretion or an overproduction of urate. These two mechanisms result in similar serum urate levels, but critically important differences in how urate is handled in the kidney and resulting tubular urate levels. To better understand altered gene expression by divergent renal handling of urate in each subtype of HUA, we compared transcriptional profiles of kidneys of two functionally different mouse models of HUA. The underexcretion model is our well established ABCG2‐Q140K knock‐in mouse, which inserts the human pathological variant Q141K into the orthologous position of the mouse Abcg2 gene. This causes decreased secretion of urate, leading to an increase in serum urate in male mice only. The overproduction model is a novel inducible knock‐out of the urate metabolizing gene uricase (UOX‐iKO), which renders both male (M) and female (F) mice unable to metabolize urate, which increases circulating levels to a similar degree seen in HUA humans. Here, UOX‐iKO mice of both sexes were induced at 9 weeks of age, and 2 weeks later, UOX‐iKO mice had serum urate levels similar to age matched ABCG2‐Q140K M mice. These UOX‐iKO mice had increased overall urinary urate excretion (UUE), as well as increased fractional excretion of urate (FEUA) in both M and F, implying higher tubular urate, consistent with urate overproduction. In contrast, ABCG2‐Q140K mice demonstrated no change in overall UUE, with a decrease in FEUA seen in M only, implying lower tubular urate, consistent with urate underexcretion. Next, we harvested kidneys from M and F mice of both HUA models and appropriate controls, followed by RNA‐Seq. To determine pathways altered by HUA, we utilized pathway analysis (DAVID Bioinformatics Resource 6.8) on all significant differentially expressed genes (DESeq2, p &lt; 0.05, FDR &lt; 0.1). Both models showed similar alterations in gene expression, with approximately 10% of all differentially expressed genes from all 3 groups of HUA mice clustered into metabolic pathways, including genes involved in steroid and amino acid metabolism. M HUA mice of both models also shared differential expression of genes involved in glutathione and fatty acid metabolism. We hypothesize that although luminal urate differs between the two models, the intracellular urate values in the proximal tubule cells will be similarly elevated. This elevation must be influencing the observed changes in metabolism related gene expression. To begin to elucidate urate dependent metabolic regulators, we next explored which transcription factors (TFs) may be driving this differential expression (Enrichr enrichment analysis) and found 2 TFs shared by all 3 HUA groups: Gata2 and Tcf3, with 2 more TFs, Sox2 and Nanog, in both M HUA mice. In conclusion, we found that models of both classical types of HUA alter renal metabolic pathways. We have also identified 2 candidate TFs that may be directly affected by urate, which could drive transcriptional changes in response to HUA. Additional experiments are required to determine the effect of urate itself on the activity of these TFs, as well as mechanistic studies to explore the effects of altered intracellular urate levels. Further elucidation these interactions may lead to improved understanding of urate homeostasis and new insights into HUA treatment.

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.

THU0410 COMPANION IMMUNOSUPPRESSION WITH AZATHIOPRINE INCREASES THE FREQUENCY OF PERSISTENT RESPONSIVENESS TO PEGLOTICASE IN PATIENTS WITH CHRONIC REFRACTORY GOUT

Background:Pegloticase is a mammalian recombinant uricase coupled to monomethoxy polyethylene glycol that is approved in the US for treatment of patients with chronic refractory gout and causes profound reductions in serum urate. However, treatment with pegloticase is limited by the induction of anti-drug antibodies and loss of responsiveness in nearly half of treated patients.Objectives:The goal of this study was to determine whether co-therapy with azathioprine (AZA) would increase the frequency of chronic refractory gout patients who had persistent urate lowering from pegloticase therapy.Methods:This open label multicenter study enrolled subjects with chronic gout who failed to lower serum urate to &lt;6 mg/dL despite medically indicated doses of urate lowering therapy (NCT02598596). Patients were screened for adequate levels of the AZA metabolizing enzyme thiopurine methyl transferase and then started on daily oral AZA 1.25 mg/kg for 1 week and then 2.5 mg/kg for the remainder of the trial. Blood levels of AZA metabolites 6-thioguanine and 6-methylmercaptopurine were measured biweekly. After receiving 2 weeks of AZA, patients were started on pegloticase (8 mg IV) and were treated biweekly for 24 weeks. The primary endpoint was the persistent lowering of serum urate to &lt;6 mg/dL at the last three consecutive study visits. Patients who had an increase in serum urate to &gt;6 mg/dL while on therapy did not receive additional pegloticase. All patients received infusion prophylaxis with hydrocortisone as well as gout flare prophylaxis.Results:To date, 12 patients have been enrolled. All patients were male, 75% white and 25% African American. Mean age was 62.4 ± 14.7 years, the mean BMI was 31.1 ± 4.5 and the mean duration of gout was 13.8 ± 9.2 years. At baseline, all patients had visible tophi; 58.3% suffered from gout flares; 81.8% had hypertension; 45.5% had dyslipidemia and 9.0% had coronary artery disease. Of the 12 patients, 6 have completed the full course of treatment with persistent urate lowering and 2 remain on treatment also with persistent urate lowering (figure). 2 patients lost the urate lowering effect, both after 2 doses of pegloticase, and did not receive additional therapy. 1 patient experienced an infusion reaction during the first dose (1 infusion reaction in 90 infusions [1.1%] in the entire trial to date) and 1 subject had subjective symptoms of AZA intolerance with no laboratory abnormalities; these subjects discontinued the study and were not evaluable for the endpoint. No adverse events related to AZA were reported and gout flares were noted in 6 subjects (mean 1.5 flares/patient with flares).Conclusion:AZA can be used safely in subjects with chronic refractory gout and appears to increase the frequency of subjects experiencing long term lowering of serum urate.

Repeated measurements of serum urate and mortality: a prospective cohort study of 152,358 individuals over 8\xa0years of follow-up

BackgroundLongitudinal evidence on change of serum urate level with mortality risk is limited as prior studies have a measurement of serum urate at a single time point. Further, the combined effect of serum urate and systemic inflammation on mortality is unknown.MethodsWe conducted a prospective cohort study of 152,358 participants (122,045 men and 30,313 women) with repeated measurements of serum urate in 2006, 2008, 2010, and 2012 (107,751 participants had all four measurements of serum urate). We used the Cox proportional hazard model to examine the association between cumulative average and changes in serum urate with mortality. The combined effect of serum urate and systemic inflammation was determined by testing the interaction of serum urate and high-sensitive C-reactive protein (hs-CRP) in relation to mortality risk.ResultsDuring a median follow-up of 8.7 (interquartile range 6.3–9.2) years, we identified 7564 all-cause deaths, 1763 CVD deaths, 1706 cancer deaths, and 1572 other deaths. We observed U-shaped relationships of cumulative average serum urate with all-cause mortality, cardiovascular mortality, and other mortalities. Compared with participants with stable serum urate, those with greater increases in serum urate had a 1.7-fold elevated mortality (hazard ratio (HR) = 1.66, 95% confidence interval (CI) = 1.49–1.84), and those with decreased serum urate had a 2-fold elevated mortality risk (HR = 2.14, 95% CI 1.93–2.37). Participants with both hyperuricemia and hs-CRP had 1.6 times higher mortality, compared with those with low serum urate and hs-CRP levels (HR = 1.56, 95% CI 1.37–1.76).ConclusionsWe observed a U-shaped relationship of long-term cumulative average serum urate with all-cause mortality, cardiovascular mortality, and other mortalities. Compared with participants with relatively stable serum urate levels, a greater increase or decrease in serum urate was associated with elevated mortality. Participants with both hyperuricemia and high systemic inflammation had the greatest mortality risk compared with those with low serum urate and low hs-CRP levels.

Sex differences by design and outcome in the Safety of Urate Elevation in PD (SURE-PD) trial.

To investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine. The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation for up to 2 years. Parkinsonism, serum urate, and plasma antioxidant capacity were measured at baseline and repeatedly on treatment; CSF urate was assessed once, at 3 months. Here in secondary analyses results are stratified by sex. Inosine produced an absolute increase in average serum urate from baseline that was 50% greater in women (3.0 mg/dL) than in men (2.0 mg/dL), consistent with expected lower baseline levels in women. Similarly, only among women was CSF urate significantly greater on mild or moderate inosine (+87% [p < 0.001] and +98% [p < 0.001], respectively) than on placebo (in contrast to men: +10% [p = 0.6] and +14% [p = 0.4], respectively). Women in the higher inosine dosing group showed a 7.0 Unified Parkinson's Disease Rating Scale (UPDRS) points/year lower rate of decline vs placebo (p = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate (r = -0.52; p = 0.001), and with greater increases in plasma antioxidant capacity (r = -0.44; p = 0.006). No significant associations were observed in men. Inosine produced greater increases in serum and CSF urate in women compared to men in the SURE-PD trial, consistent with the study's design and with preliminary evidence for slower clinical decline in early PD among women treated with urate-elevating doses of inosine. NCT00833690. This study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.

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...

Fructose malabsorption in people with and without gout: A case-control study.

Higher fructose intake has been associated with hyperuricaemia and gout. Some individuals malabsorb fructose in the small intestine. The aims of this study were to determine the rate of fructose malabsorption and the effects of gout and fructose malabsorption on serum urate in people with and without gout. A total of 100 people with gout (cases) were age and gender matched with one control without gout. After a low fructose diet, fructose malabsorption was measured using a hydrogen and methane breath test with a 35g fructose load. In a subgroup of 35 cases and 35 controls, serum urate response to the fructose load over 240 minutes was measured. There was no significant difference in the rate of fructose malabsorption between cases and controls (48% vs. 52%; p = 0.67). Cases had a significantly lower mean (SEM) serum urate cumulative incremental concentration from baseline-240 minutes (iAUC0-240) compared to controls 0.97 (0.56) vs. 4.78 (0.55); p < 0.001. Cmax was significantly lower in cases compared to controls [0.38 (0.003) vs. 0.40 (0.003); p < 0.001]. 95% of cases were receiving allopurinol. There was no significant difference between iAUC0-240 or Cmax for malabsorbers compared to normal absorbers irrespective of case-control status. The mean (SEM) increase in serum urate between baseline and 30 minutes was 0.04 (0.004)mmol/l in the controls compared to 0.009 (0.002) in the cases (p < 0.001). The rates of fructose malabsorption are similar in people with and without gout. Allopurinol inhibits the increase in serum urate induced by a fructose load suggesting that people with gout receiving allopurinol may not need to restrict dietary intake of fructose.

Positive association of tomato consumption with serum urate: support for tomato consumption as an anecdotal trigger of gout flares.

BackgroundGout is a consequence of an innate immune reaction to monosodium urate crystals deposited in joints. Acute gout attacks can be triggered by dietary factors that are themselves associated with serum urate levels. Tomato consumption is an anecdotal trigger of gout flares. This study aimed to measure the frequency of tomato consumption as a self-reported trigger of gout attacks in a large New Zealand sample set, and to test the hypothesis that tomato consumption is associated with serum urate levels.MethodsTwo thousand fifty one New Zealanders (of Māori, Pacific Island, European or other ancestry) with clinically-ascertained gout were asked about gout trigger foods. European individuals from the Atherosclerosis Risk In Communities (ARIC; n = 7517) Study, Cardiovascular Health Study (CHS; n = 2151) and Framingham Heart Study (FHS; n = 3052) were used to test, in multivariate-adjusted analyses, for association between serum urate and tomato intake.ResultsSeventy one percent of people with gout reported having ≥1 gout trigger food. Of these 20 % specifically mentioned tomatoes, the 4th most commonly reported trigger food. There was association between tomato intake and serum urate levels in the ARIC, CHS and FHS combined cohort (β = 0.66 μmolL−1 increase in serum urate per additional serve per week; P = 0.006) - evident in both sexes (men: β = 0.84 μmolL−1, P = 0.035; women: β = 0.59 μmolL −1, P = 0.041).ConclusionsWhile our descriptive and observational data are unable to support the claim that tomato consumption is a trigger of gout attacks, the positive association between tomato consumption and serum urate levels suggests that the self-reporting of tomatoes as a dietary trigger by people with gout has a biological basis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-015-0661-8) contains supplementary material, which is available to authorized users.

Interaction of Inflammation, Hyperuricemia, and the Prevalence of Hypertension Among Adults Free of Metabolic Syndrome: NHANES 2009–2010

BackgroundHyperuricemia and markers of inflammation are correlated with the risk for hypertension. Whether hyperuricemia has any impact on the association between C‐reactive protein (CRP) and hypertension is not known.Methods and ResultsWe analyzed cross‐sectional data from the National Health and Nutrition Examination Survey, 2009–2010, using ordinary least squares and logistic regression models. Those who met the criteria for metabolic syndrome, had self‐reported gout, or were <20 years old were excluded. For each 1‐SD increase in serum urate, the serum CRP concentration was 20% higher in unadjusted linear regression models and 13% higher in multivariable linear regression models, after accounting for the effects of age, sex, race, socioeconomic and educational strata, renal function, lipids, smoking, and body mass index. In multivariable models adjusting for the same covariates, hyperuricemia was associated with hypertension with an odds ratio of 2.21 (1.71 to 2.85). When analyzed separately, this was observed in men and women. In multivariable analyses of the overall sample, elevated CRP levels were not associated with hypertension.ConclusionsAmong adults free of metabolic syndrome, elevated uric acid, but not elevated CRP, is independently associated with prevalent hypertension.

Population-specific influence of SLC2A9 genotype on the acute hyperuricaemic response to a fructose load

BackgroundSLC2A9 is a strong genetic risk factor for hyperuricaemia and gout. SLC2A9 (GLUT9) is a high capacity urate transporter and reportedly transports glucose and fructose. Intake of fructose-containing beverages is...

Serum urate association with hypertension in young adults: analysis from the Coronary Artery Risk Development in Young Adults cohort

ObjectiveTo determine if serum urate concentration is associated with development of hypertension in young adults.MethodsRetrospective cohort analysis from 4752 participants with available serum urate and without hypertension at baseline from...

Serum uric acid predicts changes in reports of non-gouty chronic pain: a prospective study among women with inflammatory and non-inflammatory pain

Widespread pain has earlier been associated with an increase in serum urate (SU). The aim of this study was to longitudinally study the relation between changes in pain reporting and the level of SU among women with chronic pain. Consecutive female patients (n = 124; aged 20-70 years), at rheumatology and rehabilitation practices, with chronic musculoskeletal pain of different origins were followed for 1 year with repeated blood samples and questionnaires. Complete data were obtained from 107 individuals. Factors that predicted an increase in pain extension during 12 months were studied in a logistic regression model. Changes in SU showed a significant correlation (r = 0.36) with changes in the number of reported pain locations. An initially high SU level (OR = 4.46), frequent use of alcohol (OR = 1.32) and a high number of pain locations (OR = 1.24) independently predicted an increase in pain extension during 12 months, whereas the use of steroids (OR = 0.21) in patients with inflammatory disorders resulted in a decreased number of reported pain locations. A relative increase in SU in combination with report of a high number of pain locations turned out to be a risk factor of increased pain extension in a cohort of women with chronic non-gouty pain followed during 1 year. The importance of SU in relation to chronic pain and its prognosis needs to be validated in larger studies.

Moderate-intensity exercise associated with ketogenic diet. A model for the study of ammonia metabolism?

Introduction: Exercise has been used as a model to study the metabolism of ammonia (NH 3 + NH 4 + ), which is highly toxic to the central nervous system. A ketogenic diet leads to several metabolic adaptations to maintain the ATP/ ADP ratio, including a lack of glycogen reservoirs, the use of amino acids as carbon skeleton donors and increased -oxidation of fatty acids. The formation of ammonia during high-intensity exercise is well studied, but its role in moderate-intensity exercise remains unclear. Here we investigate ammonia metabolism during moderate-intensity exercise associated with a ketogenic diet as a model system. Materials and Methods: Athletes (n=7) were physically evaluated and had their maximum oxygen consumption (VO 2max ) and heart rate (HR max ) determined. The subjects remained on a ketogenic diet 72h prior to exercise. They then exercised for 60min at a power output of 60% of that at VO 2max , and at 70%-75% of HR max . Results: Basal ammonemia increased by 35% due to dietetic modifi cations, while exercise caused a 250% increase in ammonemia in parallel with this effect. Uremia was increased by 60% due to the ketogenic diet without response to exercise. We measured a 10% increase in serum urate that did not change during the exercise protocol. No changes were found in glycemia or lactatemia. Discussion: Our data suggest that moderate-intensity exercise associated with a ketogenic diet can be used to study the increase in ammonemia and as a model to understand ammonia metabolism during metabolic stress.

Metabolic and orthostatic blood pressure responses to a low-sodium diet in elderly hypertensives

In view of the concern regarding the potential risks and benefits of sodium restriction, the effect on biochemical and orthostatic responses from a moderate reduction in sodium intake in elderly persons that is sufficient to lower systolic blood pressure (SBP) was examined. Seventeen hypertensive subjects aged 65-79 years entered a double-blind randomized placebo controlled cross-over trial of a low sodium diet plus placebo tablets vs a low sodium diet plus sodium tablets (80 mmols/day) each for 5 weeks. At the end of high and low sodium periods, two 24-h urine collections and venous blood samples were undertaken and supine and standing BPs were recorded. On the low compared to the high sodium phase (urinary sodium excretion 95 +/- 36 vs 174 +/- 40 mmols/24-h, respectively), clinic supine SBP fell by 8 mm Hg (95% CI: 1-15 mm Hg, P< 0.05) and diastolic BP (DBP) by 1 mm Hg (CI: -3 to 5 mm Hg); there was no change in total LDL- and HDL-cholesterol and triglyceride levels, serum calcium, phosphate, parathyroid hormone, glucose, creatinine clearance or urinary albumin excretion rate. Serum urate was significantly higher during the low compared to high sodium intake (304 +/- 56 vs 277 +/- 44 micromols/l). Orthostatic BP responses during the high and low sodium intakes were unchanged. In summary, after 5 weeks of moderate sodium restriction no adverse effects other than an increase in serum urate was seen in elderly hypertensive persons.

Enalapril versus bendroflumethiazide in type 2 diabetes complicated by hypertension

In a double-blind, double-dummy, randomized, multi-centre study, the effects of bendroflumethiazide vs. enalapril on blood pressure, glycaemic control, lipoprotein concentrations and albuminuria were compared in non-proteinuric, hypertensive type 2 diabetic patients; they were treated for 20 weeks with either bendroflumethiazide 2.5-5.0 mg (n = 59) or enalapril 10-20 mg (n = 55). Age, fasting plasma glucose, HbA1c and BMI were similar in the groups. Systolic and diastolic blood pressure were reduced in both groups. Bendroflumethiazide was accompanied by minor but significant elevations in fasting plasma glucose and serum C-peptide. HbA1c was increased during both treatments. Lipoproteins and urinary albumin/creatinine ratio were stable. Bendroflumethiazide caused a decrease in serum potassium and an increase in serum urate. No significant correlations were observed between the decline in blood pressure and changes in the metabolic risk factors. Baseline levels of age, sex, BMI, blood pressure or urinary albumin/creatinine ratio were not related to changes in blood pressure, metabolic parameters or urinary albumin/creatinine ratio.

Plasma ionized calcium and cardiovascular risk factors in mild primary hyperparathyroidism: effects of long-term treatment with active vitamin D (alphacalcidol).

Primary hyperparathyroidism (HPT) has been associated with hypertension, hyperinsulinaemia, hypertriglyceridaemia and hyperuricaemia. In the present study, plasma ionized calcium (Ca2+) was studied in relation to cardiovascular risk factors in 20 subjects with mild hypertension. Plasma Ca2+ was found to be negatively correlated with fasting serum insulin, triglycerides and urate, and with diastolic blood pressure (DBP). However, after the interaction of the different risk factors had been taken into account in the multiple regression analysis, only the relationship between Ca2+ and serum insulin was significant (r = 0.55, P less than 0.01). In a previous double-blind, placebo-controlled study 1 micrograms alphacalcidol, a synthetic analogue of 1,25 dihydroxy-vitamin D3, induced a decrease in blood pressure in mild HPT subjects. In the present study, the highest dose that did not further aggravate the hypercalcaemia was given in a long-term study over a 12-month period to 18 mild HPT subjects (average dose, 1.75 micrograms daily). The treatment induced a reduction in body weight of 0.9 kg (P less than 0.05) and an increase in serum urate from 330 +/- 92 to 380 +/- 104 mmol l-1 (P less than 0.01). A reduction in blood pressure was only observed at the end of the study, from 142 +/- 17/86.6 +/- 9.1 to 139 +/- 13/82.9 +/- 8.9 mmHg (P less than 0.05 for DBP). The reduction in systolic blood pressure was significantly correlated with the reduction in body weight induced by treatment (r = 0.63, P less than 0.02). No consistent changes in glucose or lipid metabolism were induced by treatment.

Renal Excretion of Uric Acid and its Relation to Relapse and Remission in Acute Myeloid Leukaemia

The role of the kidney in uric acid homeostasis was investigated in 11 patients with acute myeloid leukaemia. Renal clearance studies were performed in all patients before and after the first course of anti-leukaemic therapy; in 5 patients at remission and in 2 of these during relapse. Urinary excretion of uric acid was much higher at lower serum urate levels in leukaemic patients than in normal subjects. The main renal regulatory mechanism of urate excretion appeared to be operated through variations in the rate of tubular secretion of urate (TSurate); with an increase in TSurate during anti-leukaemic therapy and during relapse. Proximal renal tubular dysfunction developed in all patients and large quantities of urate escaped reabsorption in the renal tubule during active disease. The size of the fraction of urate excretion attributable to incomplete tubular reabsorption was unpredictable, but often increased after chemotherapy and during relapse with a fall in the serum urate level and fell during remission with an increase in serum urate. This component of urinary excretion of urate interfered with the usual dependence of TSurate on serum urate, with the result that the urate profile of remission (normal serum urate and low TSurate) could be distinguished from that of relapse (low serum urate and high TSurate).

Effects of food, fast and alcohol on serum uric acid and acute attacks of gout

The interrelationship of the effects of brief periods of fasting and of alcohol on uric acid metabolism has been investigated in nine gouty patients and in two normouricemic subjects. There were appreciable elevations in serum urate concentration after one and two day fasts, which were accompanied by increases in both serum beta-hydroxybutyrate and blood acetoacetate. The rise in serum urate could be accounted for in most cases by a diminution in the urinary output of uric acid, which was presumably the result of inhibition, by the elevated ketone levels, of urate excretion by the tubules. The administration of from 68 to 100 gm. of ethyl alcohol together with a low purine diet produced only minor changes in serum urate levels and urinary excretion of uric acid. Larger doses of alcohol (112 to 135 gm.) given with food led to significant increases in blood lactate concentration, diminution in urinary uric acid output and hyperuricemia. When the same (smaller) amounts of alcohol which had been found to be without effect on serum urate levels were taken during brief periods of fasting, there was an elevation in serum urate levels which was slightly greater than that observed after fasting alone. This was accompanied by greater increases in blood lactate than observed after the administration of alcohol with food, and greater increases in serum beta-hydroxybutyrate than observed after an equivalent period of fasting alone. It appears that the combination of fasting and ethyl alcohol may be additive or mutually potentiating with respect to the effects of each of these factors on uric acid metabolism. Eight of the nine patients experienced one or more acute attacks of gout during the course of these studies. In the majority of cases the onset of the attack appeared to be related to rapid fluctuations in serum urate levels induced by fasting or by fasting together with alcohol ingestion. Serum urate levels tended to remain stable during and immediately after these attacks, giving little or no indication of the changes which had preceded the onset of acute gouty-arthritis. Although treatment with probenecid in two cases produced the expected uricosuria, it did not prevent the increase in serum urate induced by fasting and alcohol. The patient with gout should be cautioned to avoid prolonged fasting and other situations which produce rapid changes in serum urate concentration. However, our gouty patients do not go out to fast, but to drink. Unfortunately the alcoholic bout often continues in the absence of food, thus resulting in a combination of metabolic changes which often lead to an acute attack.