Quantitative Estimation of Urate Transport in Nephrons in Relation to Urinary Excretion Employing Benzbromarone-Loading Urate Clearance Tests in Cases of Hyperuricemia

Abstract

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 – R₁) + TSR}(1 – R₂) was designed to approximate mathematically urate transport in nephrons, where R₁ = urate reabsorption ratio; R₂ = 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 (R₁, R₂, 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_uaBBR(∞) was calculated from the ratio of C_uaBBR(100)/C_ua. Results: Before BBR administration, points satisfying the equation on the contour line for R₁ = 0.99 were highly dense in the region R₂ = 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 R₁ and R₂, but TSR was unchanged. Under the condition that R₁ = 1 and R₂ = 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_uaBBR(∞) = TSR was deduced from the equation at R₁ = 1 and R₂ = 0. In addition, TSR of the point under the condition that R₁ = 1 and R₂ = 0 on the graph agreed with TSR for the dense region at excess BBR. TSR was thus considered approximately equivalent to C_uaBBR(∞), which could be determined from a BBR-loading C_ua test. Approximate values for urate glomerular filtration, urate reabsorption, UTS, urate postsecretory reabsorption (UR₂), 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 UR₂ in HU than in NC. This enhanced difference resulted in a 15.4% decrease in U_ex for HU. Conclusion: Increased UR₂ may represent the main cause of urate underexcretion ...

Variation of Urate Transport in the Nephrons in Subtypes of Hyperuricemia

“…Significant differences in the urate transport coefficients were noted between the HU and the NC [7], but more marked differences were found between the UE and the OP (table 1). In terms of urate transport, the UE were characterized by the lowest TSR and UTS, by the highest R 2 , and subsequently by the lowest Uex in the subtypes of HU.…”

“…Ccr showed a significantly higher correlation with TSR, but a lower one with R 2 . High-grade correlation coefficients were obtained between UTS and TSR (r = 0.773, p < 0.0001), both of which are closely related to urate secretion, and UTS was calculated as a product of TSR and Sua [7]. A relationship similar to that between UTS and TSR was also seen for UR 2 and R 2 (r = 0.655, p < 0.0001), both of which are closely related to urate postsecretory reabsorption, and UR 2 is a product of (0.01 UGF + UTS) and R 2 [7].…”

“…All patients provided written informed consent prior to enrollment. Cua, creatinine clearance (Ccr) and Cua determined after administering 100 mg of BBR [CuaBBR(100)] were determined using the BBR-loading urate clearance test as reported previously [7,8]. Urate transport coefficients such as urate glomerular filtration (UGF), urate reabsorption, urate reabsorption rate (R 1 ), urate tubular secretion (UTS), tubular secretion rate (TSR), urate postsecretory reabsorption (UR 2 ) and urate postsecretory reabsorption rate (R 2 ) as well as calculated urinary urate excretion (Uex) were calculated as reported previously [7].…”

“…Since urate is mainly excreted from the nephrons, considerable differences might be found in urate transport in the nephrons between UE and OP, reflecting the differences in urate metabolism between these types. To understand the pathophysiology of urate underexcretion in HU in greater detail, we have investigated quantitative estimation of urate transport in the nephrons employing the benzbromarone (BBR)-loading urate clearance test [7,8]. Significant differences have previously been noted in urate transport between HU and normal controls (NC) [7], but more marked differences in urate transport were found between UE and OP.…”

“…To understand the pathophysiology of urate underexcretion in HU in greater detail, we have investigated quantitative estimation of urate transport in the nephrons employing the benzbromarone (BBR)-loading urate clearance test [7,8]. Significant differences have previously been noted in urate transport between HU and normal controls (NC) [7], but more marked differences in urate transport were found between UE and OP. Based on these findings, the relationship between urate transport and Uua and the mechanisms underlying urate underexcretion in HU, particularly in UE, were investigated.…”