Decreased extra-renal urate excretion is a common cause of hyperuricemia

Abstract

ABCG2, also known as BCRP, is a high-capacity urate exporter, the dysfunction of which raises gout/hyperuricemia risk. Generally, hyperuricemia has been classified into urate 'overproduction type' and/or 'underexcretion type' based solely on renal urate excretion, without considering an extra-renal pathway. Here we show that decreased extra-renal urate excretion caused by ABCG2 dysfunction is a common mechanism of hyperuricemia. Clinical parameters, including urinary urate excretion, are examined in 644 male outpatients with hyperuricemia. Paradoxically, ABCG2 export dysfunction significantly increases urinary urate excretion and risk ratio of urate overproduction. Abcg2-knockout mice show increased serum uric acid levels and renal urate excretion, and decreased intestinal urate excretion. Together with high ABCG2 expression in extra-renal tissues, our data suggest that the 'overproduction type' in the current concept of hyperuricemia be renamed 'renal overload type', which consists of two subtypes-'extra-renal urate underexcretion' and genuine 'urate overproduction'-providing a new concept valuable for the treatment of hyperuricemia and gout.

Figure 1. Current classification of hyperuricemia.

Classification of hyperuricemia is based on UUE and fractional excretion of urate (FE_UA). In this study, patients were classified as overproduction hyperuricemia, when their UUE was over 25.0 mg h⁻¹/1.73 m² (600 mg per day/1.73 m²). Those who had FE_UA under 5.5% were classified as underexcretion hyperuricemia. Combined type was classified when their UUE and FE_UA met the criteria of both overproduction and underexcretion hyperuricemia. Patients who met the single criterion of overproduction hyperuricemia, excluding combined type, were defined as overproduction type. In addition to the types shown in this figure, there is a 'normal type' whose UUE is ≤25 mg h⁻¹/1.73 m² and FE_UA is ≥5.5%. UUE unit, mg h⁻¹/1.73 m².

Figure 2. Increase of UUE and the frequency of overproduction hyperuricemia by ABCG2 dysfunction.

(a) UUE according to each ABCG2 function (n=644). Patients with hyperuricemia were divided into four groups by their estimated ABCG2 functions, that is, full function, 3/4 function, 1/2 function and ≤1/4 function. UUE showed an inverse association with ABCG2 functions (P=3.60×10⁻¹⁰ by simple linear regression analysis). All bars show mean±s.e.m. (b) Frequency of 'overproduction' hyperuricemia according to each ABCG2 function. 'Overproduction' hyperuricemia consists of overproduction type and combined type.

Figure 3. Urate excretion via Abcg2 in a mouse model.

(a) Concentration-dependent urate transport via Abcg2 (n=3). (b) Effect of oxonate on Abcg2-mediated urate transport (n=3). (c–e, g, h) In vivo study using Abcg2-knockout and wild-type mice. (c) Serum uric acid (SUA) levels (n=19–20). ***P=8.8×10⁻⁶. (d) Urinary excretion of urate (n=10–11). ***P=4.1×10⁻⁴ (e) Time course of intestinal urate excretion (n=4). ***P<0.001; **P=0.0066; *P=0.021. (f) Transintestinal urate transport (n=3–4). *P=0.037 and 0.034 for 20 min and 30 min, respectively. (g) Urate excretion in intestine and bile (n=3–4). ***P=3.6×10⁻⁴. All bars show means±s.e.m. P values were obtained by Student's t-test. NS, not significant. (h) Relative contribution of urinary, intestinal and biliary urate excretion pathways.

Figure 4. Pathophysiological model and proposed new classification of hyperuricemia.

Hyperuricemia is currently classified into urate 'overproduction type' (A), 'renal underexcretion type' (B), and combined type. Taking extra-renal urate excretion into account, we propose a testable model by which 'overproduction type' be renamed 'renal overload type' (A), consisting of two subtypes, genuine 'overproduction' (A1) and 'extra-renal underexcretion' (A2).