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Background: Hyperuricemia cases (HU) can be classified into four subgroups by combining the two main causes of hyperuricemia, i.e. urate underexcretion and overproduction. These subgroups are as follows: underexcretion-type cases (UE); overproduction-type cases (OP); combined-type cases, and normal-type cases. Since urinary urate excretion (Uua) and urate clearance differ significantly between UE and OP, urate transport in the nephrons and the intratubular urate contents might also differ. Such differences might help clarify the pathophysiology of urate underexcretion in subgroups of hyperuricemia, and thus reveal its underlying mechanisms. Methods: Urate transport coefficients in each subtype of HU were determined employing the previously reported benzbromarone-loading urate clearance tests. The subtype cases of HU were plotted on a graph of urate transport coefficients versus Uua as coordinates. The characteristic features in the distribution of subtype cases on graphs were analyzed in relation to Uua. Results: The mean (±standard error) tubular secretion rate (TSR) in the UE (48.7 ± 1.7 ml/min) was significantly lower and the postsecretory urate reabsorption rate (R2) in the UE (0.904 ± 0.004) was significantly higher than those in the normal controls (78.0 ± 2.1 ml/min and 0.877 ± 0.003) or the OP (61.1 ± 3.2 ml/min and 0.861 ± 0.009). Decrements of TSR and increments of R2 in the UE were largest in the subtypes of the HU, in terms of case numbers and the deviation rate of the group. Conversely, decrements of TSR and increments of R2 were smallest in the OP. A significant correlation was identified between TSR and Uua (r = 0.345, p < 0.0001), and a significant negative correlation was also found between R2 and Uua (r = -0.393, p < 0.0001). Conclusion: In the UE, hyperuricemia is induced mainly by urate underexcretion, which results from the combination of two main causes in urate transporters of the nephron: significantly lower TSR and significantly higher R2. Neither of these was observed in OP. Differences in urate transporters in subtypes of the HU might be important not only for understanding the pathophysiology and mechanisms of urate underexcretion and hyperuricemia, but also for providing a strategic therapy for hyperuricemia. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: A four-component system for urate transport in nephrons has been proposed and widely investigated by various investigators studying the mechanisms underlying urinary urate excretion. However, quantitative determinations of urate transport have not been clearly elucidated yet., Methods: The equation C(ua) = {C(cr)(1 - R(1)) + TSR}(1 - R(2)) was designed to approximate mathematically urate transport in nephrons, where R(1) = urate reabsorption ratio; R(2) = urate postsecretory reabsorption ratio; TSR = tubular secretion rate; C(ua) = urate clearance, and C(cr) = creatinine clearance. To investigate relationships between the three unknown variables (R(1), R(2), and TSR), this equation was expressed as contour lines of one unknown on a graph of the other two unknowns. Points at regular intervals on each contour line for the equation were projected onto a coordinate axis and the high-density regions corresponding to high-density intervals of a coordinate were investigated for three graph types. For benzbromarone (BBR)-loading C(ua) tests, C(ua) was determined before and after oral administration of 100 mg of BBR and C(ua)BBR(∞) was calculated from the ratio of C(ua)BBR(100)/C(ua)., Results: Before BBR administration, points satisfying the equation on the contour line for R(1) = 0.99 were highly dense in the region R(2) = 0.87-0.92 on all three graphs, corresponding to a TSR of 40-60 ml/min in hyperuricemia cases (HU). After BBR administration, the dense region was shifted in the direction of reductions in both R(1) and R(2), but TSR was unchanged. Under the condition that R(1) = 1 and R(2) = 0, urate tubular secretion (UTS) was considered equivalent to calculated urinary urate excretion (U(ex)) in a model of intratubular urate flow with excess BBR; C(ua)BBR(∞) = TSR was deduced from the equation at R(1) = 1 and R(2) = 0. In addition, TSR of the point under the condition that R(1) = 1 and R(2) = 0 on the graph agreed with TSR for the dense region at excess BBR. TSR was thus considered approximately equivalent to C(ua)BBR(∞), which could be determined from a BBR-loading C(ua) test. Approximate values for urate glomerular filtration, urate reabsorption, UTS, urate postsecretory reabsorption (UR(2)), and U(ex) were calculated as 9,610; 9,510; 4,490; 4,150, and 440 μg/min for HU and 6,890; 6,820; 4,060; 3,610, and 520 μg/min for normal controls (NC), respectively. The most marked change in HU was the decrease in TSR (32.0%) compared to that in NC, but UTS did not decrease. Calculated intratubular urate contents were reduced more by higher UR(2) in HU than in NC. This enhanced difference resulted in a 15.4% decrease in U(ex) for HU., Conclusion: Increased UR(2) may represent the main cause of urate underexcretion in HU.