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Six male patients with gout were treated with combined oral medication (febuxostat, 120 mg/d, and benzbromarone, 50 or 100 mg/d), aiming at a more rapid success of uric acid lowering treatment (ULT) compared to guideline suggestions. By combined oral medication in moderate dosage, the sUA was reduced to <2 mg/dl in all cases. We conclude that, by the treatment schedule outlined, the majority of patients with gout can be cured within 1 - 2 years, with uricase treatment being necessary very rarely only.

Purpose of Review: (a) To examine the latest information about renal tubular handling of uric acid, its genetic background and contribution to the causation of hyperuricemia. (b) To review the association of hyperuricemia, gout and chronic kidney damage and whether hyperuricemia is cause or effect of renal dysfunction., Recent Findings: The gene SLC2A9 encodes for GLUT9, an important proximal tubule transporter of uric acid. Polymorphisms of the gene have been linked to gout susceptibility and to hereditary hypouricemia. Familial childhood gout with progressive renal impairment attributable to mutations of the uromodulin (UMOD) gene is associated with reduced uromodulin in the proximal tubule cilia. Familial juvenile hyperuricemic nephropathy (FJHN) is one of three similar clinical disorders associated with uromodulin gene mutations. Genetic studies of urate transportation and of uromodulin-related nephropathy emphasize the pivotal importance of the proximal tubule in uric acid homeostasis. Studies of allopurinol and febuxostat lowering of serum urate have once again raised the tantalizing possibility that hyperuricemia is harmful to the kidneys by showing better preservation of glomerular filtration rate (GFR) in treated patients., Summary: Renal tubular handling of uric acid is dependent on tubular transporters, one of which is GLUT9. Mutations of its gene SLC2A9 are associated with aberrations of uric acid disposal. Familial hyperuricemia due to uromodulin deficiency precedes but does not cause kidney failure. Nevertheless, both allopurinol and febuxostat treatment has sustained the hypothesis that hyperuricemia itself can have an adverse impact on kidney function.

Hypertension was found in 18% of 65 patients with untreated gout, a lower prevalence than that previously reported. The clinical characteristics and renal function of these patients were compared with those of age matched groups of both normotensive gouty subjects and normouricaemic patients. The hypertensive patients had significantly greater body weights than their controls and also had a lower glomerular filtration rate. Other aspects of renal function were not significantly different between the three groups. The association of hypertension with gout and impaired renal function is complicated by many possible contributory factors and a simple cause and effect relationship is unlikely.

A reverse phase partition mode of high pressure liquid chromatography was developed for the estimation of purine, pyrimidine and pyrazolopyrimidine nucleosides and bases. This method has been applied to the investigation of purine and pyrimidine metabolism in subjects with gout and/or renal failure during allopurinol therapy. Plasma levels of hypoxanthine and xanthine were quantitated in all subjects. No significant differences were observed between healthy males and gouty subjects with or without allopurinol medication. There was a significant increase in xanthine levels in patients with gout and renal failure, or renal failure on allopurinol, and plasma levels of oxipurinol were increased, but no correlation with glomerular filtration rate (GFR) was observed. The separation method was also used to examine urines from patients with known abnormalities of purine and pyrimidine metabolism in an attempt to evaluate its usefulness as a urine screening technique.

Clinical gout and renal failure was seen in a 9-year-old girl. The family tree showed that 9 out of 11 young females in three generations suffered from hyperuricaemia and normal (n = 1), or impaired (n = 8), renal function. One set of twins occurred in each generation and there is only one living male subject. In members with renal failure there was no improvement in renal function after treatment of hyperuricaemia, and in 2 sisters oral contraceptives appeared to precipitate hypertension. This clinical picture may be more common than is generally realised because of failure to compare blood uric acid values with suitable age- and sex-matched controls. The evidence from this family suggests that hyperuricaemia preceded the development of renal failure.

Several previous studies have demonstrated an increased prevalence of gout in New Zealand Maoris. The aetiology of the hyperuricaemia and its effect on morbidity, apart from gout, are unknown. A survey of 115 Maori men of working age revealed a history of gout in 10 (8%) and asymptomatic hyperuricaemia in 26 (23%). The relationship of hyperuricaemia with obesity was confirmed. Alcohol did not make an obvious contribution to the prevalence of hyperuricaemia. Hypertension was more common and creatinine clearance lower amongst those with gout, but not significantly so. The frequency of hypertension and mean creatinine clearance were similar to that seen in asymptomatic hyperuricaemia and normouricaemia. Urate clearance was lower in the gouty and hyperuricaemic subjects. The normouricaemic Maoris had a reduced fractional urate clearance compared with normal men elsewhere. They also excreted a relatively small proportion of hydrogen as ammonium. Both these features are characteristic of gout, and suggest that the Maoris' susceptibility to hyperuricaemia has a renal mechanism. Obesity is common amongst the Maoris and accentuates their natural tendency to hyperuricaemia.

A study of renal function of 51 patients with gout and an equal number of normouricaemic controls revealed significant differences. A relative impairment of the glomerular filtration rate and urine concentrating ability in the gouty subjects could not be wholly explained on the basis of aging or hypertension. Renal dysfunction was generally mild and was not associated with specific clinical characteristics higher levels of uric acid excretion, or hypertriglyceridaemia. Gout patients excreted urine with a significantly lower pH. This was associated with a relatively high excretion of titratable acid and a deficit of ammonium excretion, which was accentuated by ingestion of an acid load. Urate clearance was significantly reduced in gout, even when expressed as a fraction of the glomerular filtration rate.

To determine whether patients with gout have a diet which is distinctive in quality or quantity a careful dietary questionnaire was posed over 7 days to 61 men with gout and 52 control subjects. The average daily intake of most nutrients, including total purine nitrogen, was similar except that the patients with gout drank significantly more alcohol. Beer was the most popular beverage, and 25 (41%) of those with gout consumed more than 60 g alcohol daily (equivalent to 2 . 5 litres of beer). The heavy drinkers had a significantly higher intake of purine nitrogen, half of which was derived from beer. Though the effect of ingested purine on the blood uric acid is difficult to estimate, it probably was sufficient to have a clinical effect, augmenting the hyperuricaemic effect of alcohol itself.

Using the Intralipid lipid tolerance test we could not demonstrate any direct effect of serum triglyceride on uric acid or any influence of hyperuricaemia on triglyceride removal. This result supports previous studies suggesting that hyperuricaemia and hypertriglyceridaemia are linked through the association of obesity and alcohol excess rather than a direct cause and effect mechanism. It was possible to demonstrate significant reductions of serum triglyceride in patients with gout by reducing either their alcohol intake or body weight. Reduction of serum uric acid by probenecid had no effect on serum triglyceride or cholesterol. Similarly, allopurinol had no significant effect on serum triglyceride, but a significant fall of serum cholesterol was observed.

This study attempted to simulate the drinking habits of gout patients. Beer or squash was drunk over a 4-hour period on two successive days by five gouty and five normouricaemic men. Serum lactate increased with beer and squash, but elevation of plasma uric acid was confined to beer drinking. Urate clearance increased with both beverages, but 24-hour uric acid excretion was accentuated only by beer. The purine content of several beers was measured and the principal constituent found to be guanosine, which is probably the most readily absorbed dietary purine. It was concluded that the hyperuricaemic effect of beer was mediated by the digestion of purines contained by the beer and by an effect of ethanol on uric acid synthesis. There was no evidence that beer taken in usual quantities reduced the renal excretion of uric acid.

In a metabolic ward study of five patients, azapropazone lowered plasma uric acid but exerted only a modest and variable uricosuric effect without altering urinary xanthine and hypoxanthine levels. An alternative mechanism other than uricosuria or xanthine oxidase inhibition must account for some of the hypouricaemic action of this drug. During the first day of treatment urine volume and pH declined sharply. In a separate investigation, 22 patients were given azapropazone and 18 were given allopurinol combined with colchicine for 3 months. Allopurinol reduced plasma uric acid more quickly but at the end of the study there was little difference in the hypouricaemic results achieved by both drugs. Recurrent gout occurred more frequently with allopurinol but side-effects were confined to those taking azapropazone. A slight rise in blood urea and creatinine and a fall in haemoglobin were also features of long-term azapropazone treatment.

Fifty-nine patients with primary gout were treated with either a combination of colchicine and allopurinol or colchicine alone. Assessments of renal function over 2 years revealed a statistically significant fall of glomerular filtration rate an urine concentrating ability in those receiving only colchicine. The renal function of patients given allopurinol did not change. Treatment with allopurinol resulted ina significant reduction of ammonium excretion, a phenomenon which could not be readily explained. Urate clearance also declined during allopurinol treatment, and the impaired urate clearance associated with gout became more evident. The most important observation was that allopurinol retarded an apparent decline of renal function. Presumably this was achieved through its hypouricaemic effect and implies that the hyperuricaemia of gouty patients is deleterious to the kidneys.

Tienilic acid is a drug with established uricosuric and hypotensive properties. We have examined its potential role as a single treatment for hyperuricaemia and hypertension, 2 disorders which are commonly associated. In 17 subjects with gout, blood uric acid levels were reduced by approximately 50%. Eleven of these patients also had hypertension which was improved by tienilic acid. However, a statistically significant effect was observed only with standing diastolic blood pressure. Side effects included acute episodes of gout in 4 patients and transient loin pain and dysuria in 1 patient. The precipitation of gouty arthritis is an acknowledged risk of all potent hypouricaemic drugs. The hazard of urate deposition in the renal tract implicit in the history of loin pain is a more serious complication. Thus, it would appear that tienilic acid is a potentially valuable drug which may have a special role in patients with hyperuricaemia and hypertension. Further study is necessary to determine how it may be best administered without the risk of renal damage. [ABSTRACT FROM PUBLISHER]