Kimiyoshi Ichida
Affiliation(s):
Department of pathophysiology
Background: Gouty kidney is caused by intratubular and interstitial urate deposition, which causes injury to the kidney parenchyma. In addition to urate deposition, uric acid itself and activation of the renin-angiotensin system by uric acid cause further intrarenal vascular damage via inflammation of vascular endothelium cells and tissue fibrosis. However, it is not clear whether asymptomatic hyperuricemia, in which uric acid deposition is initiated, causes nephropathy.
ATP-binding cassette subfamily G member 2 (ABCG2) is responsible for uric acid excretion and the dysfunction leads to increased serum urate concentration (SUA) and urinary uric acid excretion. The single nucleotide polymorphism Q141K of ABCG2 is half-functional for uric acid transport, while the Q126X is deficient in this function. In addition to common Q141K, the frequency of Q126X is relatively high among Japanese, and the approximate function of ABCG2 can be estimated from the genotypes of the two single nucleotide polymorphisms. We have identified that the uremic substance, indoxyl sulfate, is transported via ABCG2. An experiment on the survival rate of ABCG2 knockout mice with renal damage suggests that reduced ABCG2 function accelerates renal impairment.
Objective: We investigated the association between asymptomatic hyperuricemia and kidney dysfunction, and the impact of ABCG2 on this relationship.
Method: We conducted a retrospective cohort study for 1,885 Japanese adults undergoing routine healthcare follow-up between 2007 and 2017 who had eGFR ≥ 60 mL/min/1.73 m2. Of these participants, 311 had asymptomatic hyperuricemia (SUA > 7.0 mg/dL). These study participants were classified into three ABCG2 functional categories (full, 75%, and ≤50% function) using a genotype combination of Q141K and Q126X, and their trajectory of eGFR was observed. Linear mixed-effect models were used to analyze the relationship between asymptomatic hyperuricemia, ABCG2 function, and eGFR decline.
Results: Asymptomatic hyperuricemia was hardly associated with eGFR decline overall without ABCG2 classification. However, among those with CKD stage G2 (baseline eGFR ≥ 60 and < 90 mL/min/1.73 m2) and ≤50% functional ABCG2, eGFR decline was associated with asymptomatic hyperuricemia (p = 0.027). ABCG2 was not associated with reductions in kidney function when the SUA was < 6.0 mg/dL, the therapeutic target level for gouty patients. Among participants with SUA ≥ 6.0 mg/dL and CKD stage G2, ≤50% functional ABCG2 was associated with accelerated eGFR decline by approximately 1.2-fold compared with full functional ABCG2 (p = 0.015). Among the participants with SUA ≥ 6.0 mg/dL and CKD stage G2, the adjusted eGFR slopes for full, 75%, and ≤50% functional ABCG2 were -0.946 ± 0.049, -1.040 ± 0.046, and -1.148 ± 0.069 (mean ± SEM, mL/min/1.73 m2/year), respectively.
Conclusion: This study suggests that asymptomatic hyperuricemia was hardly associated with eGFR decline. However, in conditions of reduced ABCG2 function, relatively high SUA accelerates renal dysfunction, even in mild renal impairment.
Reference:
Ohashi Y, Kuriyama S, Nakano T, et al: Urate Transporter ABCG2 Function and Asymptomatic Hyperuricemia: A Retrospective Cohort Study of CKD Progression. Am J Kidney Dis 81:134-144 e1, 2023