Gout, diuretics and the kidney.

G out is a monosodium urate crystal deposition disease. Formation of the crystals requires high serum uric acid levels; the local factors responsible for their predilection for the joints are only started to be grasped. 2 Steady serum urate levels result from the balance between its production and excretion; hyperuricaemia results when formation is increased or difficulties in (mostly) renal excretion occur. In humans, urate is the final breakdown product of purine nucleotides, constituents of cellular energy stores such as ATP, and of DNA and RNA both internal or, to a lesser extent, ingested. Increased urate formation is the cause of hyperuricaemia and gout in some well defined enzymatic defects, and also occurs as a consequence of increased destruction of cells in some malignancies, polycythaemia vera or some haemolytic anaemias. Patients with increased production of urate are classified as overproducers, and detection of an increased amount of excreted urate is considered to be a good method of detecting the few patients whose gout results either from enzymatic defects— which are partial in the adult—or a tumour or other condition with a rapid cellular turnover. Two thirds of urate excretion occurs at the kidney, the remainder being excreted by the gut. In an estimated 85–90% cases, gout results from poor renal disposal of urate. Gouty patients with normal or low excretion of uric acid (underexcretors) may be candidates for treatment with uricosuric drugs with little risk of urinary calculi. Measurement of the amount of excreted urate has also been recommended to identify these patients. Measurement of the amount of excreted uric acid has been considered to have clinical implications. However, although on most occasions hyperuricaemia results from poor urate clearance in otherwise normal kidneys, its calculation appears to have little use for patient management and has received little attention in the clinical setting. But this measurement is often informative, explaining why many gouty patients develop their disease. Understanding the renal handling of urate has been hampered by the differences in transport among species. Humans—along with higher primates—differ from other mammals because they do not possess uricase, which further degrades poorly soluble uric acid into the soluble allantoin, which is easily disposed of, and also their transport of urate across renal tubular cells is a complex bidirectional process. In humans, only 5–10% of the filtered urate is finally excreted, the largest part being reabsorbed at the tubules, largely at the proximal convoluted tubule. Earlier studies had suggested that the urate is almost fully reabsorbed and that the urate excreted by the kidney is the result of tubular secretion, but more recent data suggest that secretion plays little part, and that excreted urate largely represents the filtered urate which escapes reabsorption.