The renal clearance of urate examines the efficiency of the removal of urate by the kidneys by all mechanisms available to the kidney, whereas the FCU examines the efficiency of the kidneys to remove urate relative to the creatinine clearance. Thus, FCU differs from the rate of renal excretion of urate, which examines the amount of urate removed by the kidneys per unit time. Hence, the term fractional "clearance" of urate (FCU) is perhaps a more accurate descriptor of the ratio of clearance of urate to creatinine than the alternative term sometimes used, the fractional "excretion" of urate [16
The present study established that the FCU could be derived from a spot-urine sample, thereby overcoming some of the uncertainties around the inconvenient and commonly unreliable 24-hour urine collection [15
], as well as providing a tool to examine more readily the renal tubular urate transport. FCU was unaltered by allopurinol but increased when probenecid was administered, both outcomes being consistent with the accepted mechanism of the action of these drugs (inhibition of urate synthesis by the former and, inhibition of tubular reuptake of urate by urate anion transporter 1 (URAT1) by the latter [31
The FCU was marginally higher in the afternoon than in the morning. This difference probably reflects diurnal rhythms in renal function. Vahlensieck et al
] showed that urinary urate concentrations are highest between 11 a.m. and 5 p.m., and urinary concentrations of creatinine exhibit similar circadian variation [33
]. In addition, the low FCU seen at night may be due to the relative dehydration associated with activation of the renin-angiotensin system [13
The FCU has not been examined widely in studies on urate, although it has been used in heritability studies in twins [9
] and correlations on the handling of urate in gouty patients and their relatives [34
]. A significant association has been found between a low FCU (≤6.6%) and SLC2A9 variants [11
], and thus highlights the potential of the FCU in understanding the function of SNPs in other urate transporters.
In our study, although the FCU was generally greater in women than men, statistical differences were not observed because of the small numbers of healthy female subjects in our studies. This contrasts with the literature, in which the FCU was statistically higher in women [26
]. Women are known to have lower plasma concentrations of urate because of the uricosuric effect of estrogen [35
], and hence, the incidence of gout is lower in pre- than postmenopausal women [36
FCU values are available from the literature in both healthy and hyperuricemic/gouty subjects (Table ), although FCU has generally not been emphasized in such studies. In some cases, only the renal clearances of urate, creatinine, or inulin (marker of glomerular function) were reported, and we have calculated the FCU from these data sets. The present studies also showed that the FCU values were normally distributed, contrasting with a previous study that reported a log normal distribution in healthy subjects [37
]. Our results on FCU are consistent with previous data, whereby patients with gout, on average, have a lower FCU than do those without gout. Healthy hyperuricemic patients (that is, without gout) had a lower FCU compared with normouricemic patients, this being in line with the findings of Lang et al
], whereby the mean FCU of hyperuricemic patients was significantly lower than that of normouricemic patients (4.9% versus 7.0%). It must be noted that gout is largely believed to be related to an inefficient renal clearance of urate, and only in a minority of patients is it due primarily to overproduction of urate. However, some patients with an apparent overproduction, based on the amount of urate secreted in their 24-hr urinary collection output, may also have inefficient renal clearance of urate [28
A reduced FCU was previously reported in other disease states, including familial juvenile hyperuricemic nephropathy, prerenal azotemia, and idiopathic uric acid nephrolithiasis [24
]. However, a low FCU is not diagnostic of a disease state per se
, because healthy normouricemic patients with a low FCU are not uncommon, as seen in the present study. Despite a relatively low FCU, many are able to maintain a normal plasma urate, perhaps because of relatively low synthesis of urate. Hyperuricemia was also detected in a small number of healthy subjects with normal FCUs. The clinical implication of a low FCU in an otherwise healthy individual is not known; however, we suggest that these individuals might be more susceptible subsequently to develop hyperuricaemia and gout, especially if their dietary intake of urate precursors is relatively high.
Finally, FCU is not currently proposed for routine clinical use; rather, especially the spot test can be used as a tool in studies exploring the basis for variations in renal handling of urate, including epidemiologic investigations.