Uric Acid and Estimate of Renal Function. Let's Stick Together

Hyperuricaemia refers to an abnormally high concentration of uric acid in serum [ 1 ], typically defined as >7 mg/dL (416 μmol/L) in men and >6 mg/dL in women [ 1 ]. Mean serum uric acid has increased progressively over the last century in many populations and the prevalence of hyperuricemia increases with age and is higher in men than premenopausal women [ 1 ], as oestrogen increases urate excretion by the kidneys. Hyperuricaemia is usually discussed in the context of gout, but it is increasingly recognised that serum uric acid values >5.0 mg/dL (men) or 4.5 mg/dL (postmenopausal women) are clinically relevant markers of other diseases including hypertension, chronic kidney disease (CKD), hypertriglyceridemia, obesity, atherosclerotic heart disease, and metabolic syndrome [ 1 , 2 ]. The threshold of uric acid associated with the risk of cardiovascular and renal disease is significantly lower than that suggested for the diagnosis of gout [ 3 ] while only slight increases in the levels of serum uric acid are associated with poorer blood pressure control [ 4 ] and an increase RR of cardiovascular disease beyond the SCORE risk calculation [ 5 ]. However, a large body of evidence links hyperuricaemia with the decline in renal function and to the increase in serum creatinine. The uric acid produced by the body is largely excreted by the kidney and any abnormality in the renal function can result in a significant reduction in urate excretion with a consequent increase in serum urate levels [ 6 ]. This would clearly support the hypothesis that the plasma levels of uric acid are directly related to serum creatinine and the negative prognostic impact described for hyperuricemia is actually an indirect effect of renal dysfunction/CKD, a well-known risk factor for cardiovascular diseases. This could explain the unfavourable effects of hyperuricemia in patients with heart failure where the decline in cardiac function and the extensive use of diuretics would results in a decrease in GFR with the consequent development of hyperuricemia. This elementary sequence is contradicted by the “paradoxical” results of a couple of large clinical trials in patients with heart failure [ 7 , 8 ] where the hazard ratio of all-cause and cardiovascular mortality is significantly higher in patients with preserved renal function. This evidence clearly supports the importance of uric acid production over under excretion for cardiovascular risk and clearly emphasizes the possibility that the prognostic meaning of hyperuricemia can be actually estimated by considering also renal function. An increase in uric acid levels associated with normal or slightly impaired renal function is highly suggestive of abnormalities in the urate production or tubular re-absorption that can directly and indirectly contribute to the dangerous vascular effects of hyperuricemia.