In a recent article, Perez-Ruiz et al summarize their studies of uric acid excretion in 100 men with gouty arthritis and in 72 age- and sex-matched controls (1). Two aspects of this important work seem particularly noteworthy.
The 24-hour excretion in gouty subjects (628 ± 154 mg/day/1.73 m2) covers essentially the same range as that of the matched controls (594 ± 143 mg/day/1.73 m2). Despite these apparently comparable findings, 35 of the gouty individuals were considered to be overexcreters, i.e., their excretion rate was considered to be abnormally high. My concern is that the cut-off point of 700 mg/day/1.73 m2 that was chosen here (and is widely used elsewhere) lies well within 1 standard deviation of the normal mean and therefore lacks both statistical and physiologic validity. It would be helpful to see the individual values from normal and gouty subjects plotted in parallel vertical arrays to permit a visual comparison of the frequency distributions. I suspect that it then would become clear that a more appropriate cut-off of 880 mg/day/1.73 m2 (2 standard deviations above the normal mean) would avoid categorizing as overexcretors most of the individuals so classified in this report. The control group reported by Perez-Ruiz et al is large, current, normalized to a constant body size, and well studied. It seems appropriate to use this population to reset the normal upper limit of daily uric acid excretion at 880 mg/1.73 m2 (while bearing in mind that the precision of this test is poor and no overexcretor should be so labeled on the basis of any single high value) (2).
The clearance of uric acid (Cu; in milliliter minute/1.73 meter2) (as well as its corollary the fractional excretion [FEu; in percent]) remained remarkably constant in 58 gouty patients studied before and after their hyperuricemia was controlled by allopurinol. This finding stands in marked contrast to those of previous studies of uric acid excretion in individuals studied at baseline, after allopurinol administration, or after hyperuricemia was induced by an oral bolus of yeast RNA (metaanalyzed in reference 3). Those studies consistently found the urinary excretion of uric acid to vary as an exponential function of the serum level, i.e., the efficiency of excretion increased when the serum level rose and fell when the serum did too. Is it possible to reconcile these disparate findings? I think maybe so.
A plausible hypothesis suggests that the transporter responsible for tubular reabsorption may be inducible by its substrate. Thus, more filtered urate leads to more carrier, whereas a lower burden results in less carrier. This idea is teleologically attractive (why should the tubule be burdened with more carriers than it needs?), it has abundant exemplars in the realm of enzymology, and it has been demonstrated in other transcellular transport systems (including some in the renal tubules). If this feedback system involves a significant response time, an acute urate load may overwhelm the tubular reabsorptive capacity, while an acute fall may lead to supereffective reabsorption as an excess of transporters competes for both filtered and secreted urate (it is thought that absorption and secretion may be coextensive systems within the proximal tubule) (4).
Additional support for the hypothesis may lie in the remarkably high clearance of infused uric acid (5), the marked overexcretion seen in acute leukemia and the tumor lysis syndrome (which may occur with only moderate hyperurcemia) (6), and (on the other end of the scale) the sometimes sluggish response of the serum urate level after institution of allopurinol therapy. Now that the apparent transporter has been identified and sequenced, the hypothesis of inducibility should be testable on a molecular level (7).
The relevance of this hypothesis to the earlier exponential evidence lies in the fact that past studies tended to be short term, whereas I suspect that a longer time may have elapsed between the pre- and posttherapy observations of Perez-Ruiz et al. Up- or downregulation of the reabsorptive capacity may require a substantial period after a change in the filtered load (days or weeks) before balance is restored at the previous clearance rate. Clearly, the hypothesis also implies that inefficient excretion (with resultant hyperuricemia) may be caused not by defective carriers, but by a lower setting of the undiscovered feedback system that regulates their number.
Do these new data mean that we should change the way we evaluate the renal component of our patients' hyperuricemia? I think that the best answer is yes, but not by much. It remains desirable to identify the unusual patient who significantly overexcretes urinary uric acid, and I believe the best way to do so is to screen with the Eu/GF that is easily measured in midmorning spot urine samples by taking the product of the urinary uric acid and serum creatinine and dividing by the urinary creatinine. The result is the milligrams of urinary uric acid per deciliter of glomerular filtrate or, alternatively, it may be considered the excretion rate of uric acid, in milligrams/minute, after the glomerular filtration rate (GFR) has been normalized to 100 ml/minute. The test is simple, it is uncomplicated by 24-hour collection problems, and it includes (in the GFR) a meaningful correction for differences in body size. If 2 or more such determinations are significantly elevated (greater than 0.6 mg/dl), then more extensive evaluations may be made starting with 3 24-hour collections on a low purine diet (2).
The quantitative information obtained by the Eu/GF may be extended to the qualitative realm by simply dividing it by the serum urate concentration. This yields the FEu that Perez-Ruiz et al found to be unchanged when it was examined before and after allopurinol therapy. This value is the decimal fraction of uric acid in the glomerular filtrate that is ultimately excreted in the urine. Although the bidirectional tubular transport of uric acid means that virtually all filtered urate is reabsorbed and most of the excreted molecules enter the nephron by tubular secretion, the FEu remains a useful measure of overall excretion efficiency. Again using approximately 2 standard deviations from the mean of the new Spanish data, inefficient excretion begins when the FEu falls below 4%. It must be noted here that the utility of clearance (or FEu) has long been emphasized by other observers, most notably Brian Emmerson (8).
As a final thought, may I suggest that we try to do away with the term underexcretion? Generations of medical students have been confused by the idea that overexcretion of uric acid is associated with hyperuricemia and gout, and, by the way, so is underexcretion. The fact that the first term is quantitative but the second is qualitative often escapes the naïve reader. To me, it makes sense to retain overexcretion for those unusual patients who overproduce urate with a resultant abnormally high excretion rate of uric acid. For those who cope badly with a normal urate burden, “inefficient excretion” seems a more clear and useful descriptor. Doesn't it make sense to say simply that hyperuricemia results from making too much uric acid (which we can evaluate by studying the excretion rate) and/or from clearing it inefficiently (which we evaluate by measuring the fractional excretion)?