The Treatment of Gout and Disorders of Uric Acid Metabolism with Allopurinol

Allopurinol (4-hydroxypyrazolo (3,4-d)-pyrimidine) is a potent xanthine oxidase inhibitor which inhibits the oxidation of naturally occurring oxypurines, thus decreasing uric acid formation. The clinical and metabolic effects of this agent were studied in 80 subjects with primary and secondary gout and other disorders of uric acid metabolism. Allopurinol has been universally successful in lowering the serum uric acid concentration and uric acid excretion to normal levels, while not significantly affecting the clearance of urate or other aspects of renal function. Oxypurine excretion increased concomitantly with the fall in urine uric acid. The agent is particularly valuable in the management of problems of gout with azotemia, acute uric acid nephropathy and uric acid urolithiasis. The minor side effects, clinical indications and theoretical complications are discussed.     

Antioxidant status and dialysis: Plasma and saliva antioxidant activity in patients with fluctuating urate levels

The present study is concerned with the influence of processes occurring during dialysis on the antioxidant capacity of plasma and saliva. The biological fluids were also tested for uric acid and total protein content. Before hemodialysis, plasma antioxidant status of hemodialyzed patients appears slightly higher than the corresponding status in normal subjects; after hemodialysis it is found unchanged. The result can be explained by a balance between a reduction in uric acid plasma content, due to the dialytic procedure, and an increase in protein content, possibly due to a dialysis-related hemoconcentration. Moreover, pre-dialysis total antioxidant capacity of whole saliva samples is higher than in healthy individuals and drastically decreases towards normal values following dialytic procedure. Our data indicate a certain concentration of the uric acid in the saliva of hemodialyzed patients and evidence that both total protein concentration and uric acid level show a good correlation with saliva total antioxidant capacity, suggesting that proteins are major antioxidants of this fluid. Further observations are needed to assess whether this improved saliva antioxidant ability has any consequence on the periodontal conditions of hemodialyzed subjects.     

Antioxidant status and dialysis: Plasma and saliva antioxidant activity in patients with fluctuating urate levels

The present study is concerned with the influence of processes occurring during dialysis on the antioxidant capacity of plasma and saliva. The biological fluids were also tested for uric acid and total protein content. Before hemodialysis, plasma antioxidant status of hemodialyzed patients appears slightly higher than the corresponding status in normal subjects; after hemodialysis it is found unchanged. The result can be explained by a balance between a reduction in uric acid plasma content, due to the dialytic procedure, and an increase in protein content, possibly due to a dialysis-related hemoconcentration. Moreover, pre-dialysis total antioxidant capacity of whole saliva samples is higher than in healthy individuals and drastically decreases towards normal values following dialytic procedure. Our data indicate a certain concentration of the uric acid in the saliva of hemodialyzed patients and evidence that both total protein concentration and uric acid level show a good correlation with saliva total antioxidant capacity, suggesting that proteins are major antioxidants of this fluid. Further observations are needed to assess whether this improved saliva antioxidant ability has any consequence on the periodontal conditions of hemodialyzed subjects.     

Mechanism of exercise-induced hyperuricemia

This study was designed to make clear why increases and decreases in serum uric acid levels after vigorous exercise were delayed. Eight healthy male subjects who were given allopurinol before exercise participated in this study. We performed exhaustive exercise test on bicycle ergometer, and investigated the changes in purine metabolites levels in blood and urine. Results were summarized as follow; 1) Serum uric acid concentrations did not change significantly. Urinary excretions of uric acid decreased from 30 minutes to 1 hour after exercise, and recovered thereafter. 2) Plasma oxypurines concentrations exhibited the maximum level at 1 hour after exercise, and maintained the higher levels until 7 hours after exercise. Urinary oxypurines excretions exhibited the maximum level at 1 hour after exercise, and maintained the higher levels until 24 hours after exercise. 3) Plasma inosine concentrations increased only in one subject. Plasma hypoxanthine concentrations increased significantly in all subjects. Plasma xanthine concentrations did not change. 4) Blood ammonia concentrations exhibited the maximum level at 5 minutes after exercise, and returned to basal levels at 2 hours after exercise. These observations suggest that the delays of increases and decreases in serum uric acid levels are due to that the prolonged release of hypoxanthine from skeletal muscle lead to the prolonged production of uric acid in liver.     

The Effects of Oral Salicylate on Serum Uric Acid Levels

Thirteen males and six females were given 40 grains of oral salicylate daily for six days. The serum uric acid of 16 of the 19 subjects fell, the mean post-treatment level being 1.1 mg. % less than the control mean. In five males and five females, administration of 20 grains of oral salicylate daily for six days resulted in a uniform rise of serum uric acid, the post-treatment mean being 1.4 mg. % above the pretreatment mean. Salicylate therapy in common dosage may therefore falsely elevate or depress serum uric acid levels. An accurate evaluation of a serum uric acid level can be made only if the patient is not under the influence of salicylates.     

Clearance of oxypurines in normal subjects and in gout patients subjected to a purine-free diet. Effects of allopurinol

The clearance of uric acid, hypoxanthine and xanthine has been examined in gout patients and in normal subjects compared to creatinine, after a purine-free diet. The treatment decreased the clearance in normal subjects, but showed an opposite effect in gout patients. The clearances both of uric acid, hypoxanthine and xanthine were enhanced by allopurinol. The interpretation of the observed variations is discussed.     

Association between intronic SNP in urate-anion exchanger gene, SLC22A12, and serum uric acid levels in Japanese

Serum uric acid levels are maintained by urate synthesis and excretion. URAT1 (coded by SLC22CA12) was recently proposed to be the major absorptive urate transporter protein in the kidney regulating blood urate levels. Because genetic background is known to affect serum urate levels, we hypothesized that genetic variations in SLC22A12 may predispose humans to hyperuricemia and gout. We investigated rs893006 polymorphism (GG, GT and TT) in SLC22A12 in a total of 326 Japanese subjects. Differences in clinical characteristics among the genotype groups were tested by the analysis of variance (ANOVA). In male subjects, mean serum uric acid levels were significantly different among the three genotypes. Levels in the GG genotype subjects were the highest, followed by those with the GT and TT genotypes. However, no differences between the groups were seen in the distributions of creatinine, Fasting plasma glucose (FPG), HbA(1c), total cholesterol, triglyceride, HDL cholesterol levels or BMI. A single nucleotide polymorphism (SNP) in the urate transporter gene SLC22CA12 was found to be associated with elevated serum uric acid levels among Japanese subjects. This SNP may be an independent genetic marker for predicting hyperuricemia.     

Uric Acid Levels Can Predict Metabolic Syndrome and Hypertension in Adolescents: A 10-Year Longitudinal Study

The relationships between uric acid and chronic disease risk factors such as metabolic syndrome, type 2 diabetes mellitus, and hypertension have been studied in adults. However, whether these relationships exist in adolescents is unknown. We randomly selected 8,005 subjects who were between 10 to 15 years old at baseline. Measurements of uric acid were used to predict the future occurrence of metabolic syndrome, hypertension, and type 2 diabetes. In total, 5,748 adolescents were enrolled and followed for a median of 7.2 years. Using cutoff points of uric acid for males and females (7.3 and 6.2 mg/dl, respectively), a high level of uric acid was either the second or third best predictor for hypertension in both genders (hazard ratio: 2.920 for males, 5.222 for females; p<0.05). However, uric acid levels failed to predict type 2 diabetes mellitus, and only predicted metabolic syndrome in males (hazard ratio: 1.658; p<0.05). The same results were found in multivariate adjusted analysis. In conclusion, a high level of uric acid indicated a higher likelihood of developing hypertension in both genders and metabolic syndrome in males after 10 years of follow-up. However, uric acid levels did not affect the occurrence of type 2 diabetes in both genders.     

Effects of profuse sweating induced by exercise on urinary uric acid excretion in a hot environment

In order to determine whether exercise-induced profuse sweating could reduce urinary uric acid excretion, we simulated badminton players training and measured their uric acid in urine, sweat and blood during the training period. Thirteen male volunteers who were well-trained badminton players were recruited in this study. On the first 2 days and the last 2 days of the study period none of the subjects engaged in any intense exercise- or activity-inducing profuse sweat, but they accepted routine training 2 h per day during the middle 3 days. The results show that mean serum urate levels of thirteen volunteers rose significantly on day 4, when the concentrations increased by 18.2% over day 2 (P < 0.05). The mean ten-hour urinary uric acid excretion of seven volunteers on the 3 training days was significantly less at 178.5 micromol/day and 118.3 micromol/day than those on the preceding and subsequent days of the training days, respectively (P < 0.05). Furthermore, for six volunteers, the mean ratio of clearance of uric acid to creatinine was 6.6% on day 2, which significantly decreased to 5.4% on day 4 (P < 0.05). It is concluded profuse sweating exercise results in a decrease of urinary uric acid excretion amounts and leads to increased serum uric acid after the exercise. We suggest that persons who take vigorous exercise or are exposed to hot environments need drinking enough fluids to prevent dehydration and maintain adequate urinary output. People with profuse sweat after rigorous exercise are recommended taking sports drinks containing abundant sodium in order to decrease serum uric acid.     

Serum Uric Acid and Chronic Kidney Disease: The Role of Hypertension

Background

There 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.

Methods

We 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.

Results

Each 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).

Conclusions

Our 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.     

Analysis of uric acid and oxypurines in normal subjects and in gout patients

The behavior of plasma and urine oxypurines (hypoxanthine and xanthine) and of uric acid has been studied in normal subjects and in gout patients. Oxypurines and uric acid were increased in the plasma of gout patients but only the urinary excretion of hypoxanthine was higher in this group. The interpretation of the observed variations is discussed.     

Serum lipid resistance to oxidation and uric acid levels in subjects with Down's syndrome

In subjects with Down's syndrome (DS) increased oxidative stress and consequent oxidative cell damage have been reported. The aim of this study was to assess whether the excessive production of free oxygen radicals in these subjects can affect the copper-induced lipid oxidation resistance measured in fresh whole serum. Since a significant elevation of serum uric acid levels, which is an efficient hydrophilic antioxidant, has been repeatedly reported in subjects with DS, we studied the association between increased serum uric acid levels and lipid resistance to oxidation measured directly in serum samples by monitoring the change in absorbance at 234 nm. The group of subjects with Down's syndrome consisted of 25 individuals (aged 18+/-5 years). Control group included brothers and sisters of subjects with DS (n = 25, aged 17+/-7 years). In subjects with DS, the serum lipid resistance to oxidation (lag time) was significantly higher than in controls (p<0.05) and a concomitant increase in serum uric acid levels was observed (p<0.001). A significant positive correlation between lag time and serum uric acid concentration was found in subjects with DS (r = 0.48, p<0.05), while the positive correlation in the control group was not significant. The results suggest that increased serum uric acid levels repeatedly observed in subjects with DS may be associated with an enhanced resistance of serum lipids to oxidation which is thought to play an important role in the atherogenic process.     

Effect of KC1 on renal uric acid excretion.

The effect of two days' KC1 administration per os (total amount 11 g, i.e. 140 mEq potassium) on renal uric acid excretion was studied in healthy subjects under conditions of water diuresis. A significant increase in the uric acid excretory fraction (CUA/CCr..100) was found, from 8.04% in the control test to 10.31% under experimental conditions. Elevated renal uric excretion led to a significant drop in the plasma uric acid level from 4.9 mg% to 4.2 mg% after the administration to KC1. The findings suggest that KC1 influences the tubular transport of uric acid, but the mechanism of its action is still obscure.     

High Serum Uric Acid Increases the Risk for Nonalcoholic Fatty Liver Disease: A Prospective Observational Study

Nonalcoholic fatty liver disease (NAFLD) is a common form of chronic liver disease, and serum uric acid is observed to be significantly elevated in NAFLD patients. However, whether this elevation is causal, a bystander, or a consequence of NAFLD remains unclear. We performed a population-based prospective study among the employees of Zhenhai Refining & Chemical Company Ltd., Ningbo, China to investigate whether the elevation of serum uric acid has a casual role for NAFLD. A total of 6890 initially NAFLD-free subjects were followed up for 3 years. Overall, 11.80% (813/6890) subjects developed NAFLD over 3 years of follow-up. The cumulative incidence of NAFLD increased with progressively higher baseline serum uric acid levels (the cumulative incidence was 7.2%, 9.5%, 11.5%, 13.8%, and 17.2% in quintile 1, quintile 2, 3, 4 and 5, respectively; P value for trend <0.001). Cox proportional hazards regression analyses showed that serum uric acid levels were independently and positively associated with the risk for incident NAFLD; the age-, gender- and metabolic syndrome adjusted hazard ratio (95% CI) for the subjects in quintile 2, 3, 4 and 5 versus quintile 1 was 1.18 (0.91–1.54), 1.32 (1.03–1.70), 1.39 (1.09–1.78) and 1.50 (1.18–1.92), respectively. Taken together, our prospective observational study showed that elevation of serum uric acid levels independently predicts increase risk for incident NAFLD.     

Identification of a new candidate locus for uric acid nephrolithiasis

Renal stone formation is a common multifactorial disorder, of unknown etiology, with an established genetic contribution. Lifetime risk for nephrolithiasis is approximately 10% in Western populations, and uric acid stones account for 5%-10% of all stones, depending on climatic, dietary, and ethnic differences. We studied a small, isolated founder population in Sardinia, characterized by an increased prevalence of uric acid stones, and performed a genomewide search in a deep-rooted pedigree comprising many members who formed uric acid renal stones. The pedigree was created by tracing common ancestors of affected individuals through a genealogical database based on archival records kept by the parish church since 1640. This genealogical information was used as the basis for the study strategy, involving screening for alleles shared among affected individuals, originating from common ancestors, and utilization of large pedigrees to obtain greater power for linkage detection. We performed multistep linkage and allele-sharing analyses. In the initial stage, 382 markers were typed in 14 closely related affected subjects; interesting regions were subsequently investigated in the whole sample. We identified two chromosomal regions that may harbor loci with susceptibility genes for uric acid stones. The strongest evidence was observed on 10q21-q22, where a LOD score of 3.07 was obtained for D10S1652 under an affected-only dominant model, and a LOD score of 3.90 was obtained using a dominant pseudomarker assignment. The localization was supported also by multipoint allele-sharing statistics and by haplotype analysis of familial cases and of unrelated affected subjects collected from the isolate. In the second region on 20q13.1-13.3, multipoint nonparametric scores yielded suggestive evidence in a approximately 20-cM region, and further analysis is needed to confirm and fine-map this putative locus. Replication studies are required to investigate the involvement of these regions in the genetic contribution to uric acid stone formation.     

Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase

PEG-modified recombinant mammalian urate oxidase (PEG-uricase) is being developed as a treatment for patients with chronic gout who are intolerant of, or refractory to, available therapy for controlling hyperuricemia. In an open-label phase I trial, single subcutaneous injections of PEG-uricase (4 to 24 mg) were administered to 13 such subjects (11 had tophaceous gout), whose plasma uric acid concentration (pUAc) was 11.3 ± 2.1 mg/dl (mean ± SD). By day seven after injection of PEG-uricase, pUAc had declined by an average of 7.9 mg/dl and had normalized in 11 subjects, whose mean pUAc decreased to 2.8 ± 2.2 mg/dl. At doses of 8, 12, and 24 mg, the mean pUAc at 21 days after injection remained no more than 6 mg/dl. In eight subjects, plasma uricase activity was still measurable at 21 days after injection (half-life 10.5 to 19.9 days). In the other five subjects, plasma uricase activity could not be detected beyond ten days after injection; this was associated with the appearance of relatively low-titer IgM and IgG antibodies against PEG-uricase. Unexpectedly, these antibodies were directed against PEG itself rather than the uricase protein. Three PEG antibody-positive subjects had injection-site reactions at 8 to 9 days after injection. Gout flares in six subjects were the only other significant adverse reactions, and PEG-uricase was otherwise well tolerated. A prolonged circulating life and the ability to normalize plasma uric acid in markedly hyperuricemic subjects suggest that PEG-uricase could be effective in depleting expanded tissue stores of uric acid in subjects with chronic or tophaceous gout. The development of anti-PEG antibodies, which may limit efficacy in some patients, is contrary to the general assumption that PEG is non-immunogenic. PEG immunogenicity deserves further investigation, because it has potential implications for other PEGylated therapeutic agents in clinical use.     

Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase

PEG-modified recombinant mammalian urate oxidase (PEG-uricase) is being developed as a treatment for patients with chronic gout who are intolerant of, or refractory to, available therapy for controlling hyperuricemia. In an open-label phase I trial, single subcutaneous injections of PEG-uricase (4 to 24 mg) were administered to 13 such subjects (11 had tophaceous gout), whose plasma uric acid concentration (pUAc) was 11.3 +/- 2.1 mg/dl (mean +/- SD). By day seven after injection of PEG-uricase, pUAc had declined by an average of 7.9 mg/dl and had normalized in 11 subjects, whose mean pUAc decreased to 2.8 +/- 2.2 mg/dl. At doses of 8, 12, and 24 mg, the mean pUAc at 21 days after injection remained no more than 6 mg/dl. In eight subjects, plasma uricase activity was still measurable at 21 days after injection (half-life 10.5 to 19.9 days). In the other five subjects, plasma uricase activity could not be detected beyond ten days after injection; this was associated with the appearance of relatively low-titer IgM and IgG antibodies against PEG-uricase. Unexpectedly, these antibodies were directed against PEG itself rather than the uricase protein. Three PEG antibody-positive subjects had injection-site reactions at 8 to 9 days after injection. Gout flares in six subjects were the only other significant adverse reactions, and PEG-uricase was otherwise well tolerated. A prolonged circulating life and the ability to normalize plasma uric acid in markedly hyperuricemic subjects suggest that PEG-uricase could be effective in depleting expanded tissue stores of uric acid in subjects with chronic or tophaceous gout. The development of anti-PEG antibodies, which may limit efficacy in some patients, is contrary to the general assumption that PEG is non-immunogenic. PEG immunogenicity deserves further investigation, because it has potential implications for other PEGylated therapeutic agents in clinical use.     

The association of uric acid with glucose and lipids in general population: Croatian cross-sectional study

Hyperuricemia may have an important role in metabolic syndrome, cardiovascular diseases and stroke. Elevated serum uric acid concentration has been shown to be the strong predictor of cardiovascular mortality in several recently published studies. Our aim was to determine the prevalence of hyperuricemia in general Croatian population and to investigate the association of serum uric acid with glucose and lipids. This was a retrospective cross-sectional study on 6,476 consecutive adults. Prevalence of hyperuricemia was 13.9% in general population and it was significantly higher in males, than in females (26% vs. 6%; p < 0.001). Median uric acid concentration was higher in males than in females (343 vs. 238 micromol/L; p < 0.001). Age, glucose and lipid parameters did not correlate with uric acid. In hyperuricemic subjects, increased concentrations of glucose (33.1% vs. 13.1%; p < 0.001), triglycerides (46.9% vs. 17.6%; p < 0.001), total cholesterol (69.6% vs. 51.9%; p < 0.001), LDL-cholesterol (64.5% vs. 46.4%; p < 0.001) and decreased concentration of HDL-cholesterol (24.3% vs. 13.0%; p < 0.001) were more prevalent than in subjects with normal serum concentrations of uric acid. Hyperuricemia is highly prevalent in Croatian general population and it aggregates with hyperglycemia and dyslipidemia.     

Behavior of plasma and urinary cAMP after intravenous fructose load

Increased excretion of uric acid and cAMP has been observed in many pathological conditions in man, but interrelation between behaviour of uric acid and cAMP is not well known. To investigate these aspects of purine metabolism the authors have studied behaviour of plasma and urinary cAMP in 8 subjects after intravenous rapid load of fructose (0.5 g/Kg b.w.) compared with the uric acid one. The results have shown that urinary excretion of cAMP after load of fructose is increased, but levels of plasma cAMP remain unchanged. These data confirm consensual relation between urinary uric acid and cAMP excretion, but the exact mechanism of this relation remains unexplained.     

Disposition of uric acid upon administration of ofloxacin alone and in combination with other anti-tuberculosis drugs

Disposition of uric acid upon administration of ofloxacin (O) alone and in combination with other anti-tuberculosis drugs, rifampicin (R), isoniazid (H) and pyrazinamide (Z) was studied. Twelve male healthy volunteers were investigated on four different occasions with the four drugs alone or in combinations. A partially balanced incomplete block design was adopted and the subjects were randomly allocated to each group. Uric acid concentration in urine samples excreted over 0-8 hr, were determined after coding the samples. There was significant decrease in the group receiving Z when compared to other groups. Though there was a decrease in uric acid excretion in the group receiving O, it was not statistically significant. Rifampicin and H seem to increase the uric acid excretion. The incidence of arthralgia was mainly due to Z and not due to either O or other drugs in the treatment of pulmonary tuberculosis.