Urate Transporter ABCG2 Function and Asymptomatic Hyperuricemia: A Retrospective Cohort Study of CKD Progression

Abstract

Rationale & objective: Treatment of asymptomatic hyperuricemia is not commonly implemented. However, it is unclear whether urate deposition that begins during asymptomatic hyperuricemia can induce nephropathy. Dysfunction of ATP-binding cassette subfamily G member 2 (ABCG2), a urate efflux transporter, leads to elevated serum uric acid concentration (SUA). We investigated the association between asymptomatic hyperuricemia and decreased estimated glomerular filtration rate (eGFR), and the impact of ABCG2 on this relationship.

Study design: Retrospective cohort study.

Setting & participants: 1,885 Japanese adults undergoing routine health care follow-up between 2007 and 2017 who had eGFR ≥60 mL/min/1.73 m², of which 311 had asymptomatic hyperuricemia (SUA >7.0 mg/dL). Study participants were classified into 3 categories of estimated ABCG2 function (full, 75%, and ≤50% function).

Predictors: Baseline SUA and estimated ABCG2 function.

Outcome: Change in eGFR over time.

Analytical approach: Linear mixed-effect models were used to analyze the relationship between asymptomatic hyperuricemia, ABCG2 function, and eGFR decline.

Results: Asymptomatic hyperuricemia was negligibly associated with eGFR decline overall. However, among those with eGFR 60-89 mL/min/1.73 m² and ≤50% ABCG2 function, eGFR decline was associated with asymptomatic hyperuricemia (P = 0.03). ABCG2 was not associated with eGFR reductions when the SUA was <6.0 mg/dL. Among participants with SUA ≥6.0 mg/dL and eGFR 60-89 mL/min/1.73 m², ≤50% ABCG2 function was associated with approximately 1.2-fold faster eGFR decline compared with fully functional ABCG2 (P = 0.02). Among the participants with SUA ≥6.0 mg/dL and eGFR 60-89 mL/min/1.73 m², the adjusted eGFR slopes (given as mean ± standard error of the mean, in mL/min/1.73 m² per year) were -0.946 ± 0.049, -1.040 ± 0.046, and -1.148 ± 0.069 for full, 75%, and ≤50% ABCG2 function, respectively.

Limitations: Lack of measurement of urinary urate and uremic toxins that are known to be transported by ABCG2, and no independent validation cohort.

Conclusions: Asymptomatic hyperuricemia was not associated with eGFR decline, except when in the presence of ≤50% ABCG2 function.

Plain-language summary: The urate transporter ABCG2 is a protein that regulates serum urate concentrations; when dysfunctional, it can lead to elevated serum concentrations of this compound (ie, hyperuricemia). Although persistent hyperuricemia induces gout and kidney injury, the effects on organs during the asymptomatic phase have yet to be established. Therefore, to clarify the relationship between ABCG2, asymptomatic hyperuricemia, and kidney function, we conducted a retrospective cohort study of 1,885 healthy participants, including 311 participants with asymptomatic hyperuricemia. We found that the coexistence of asymptomatic hyperuricemia and severe ABCG2 dysfunction was associated with the age-dependent decline in kidney function. We concluded that asymptomatic hyperuricemia represents a risk factor for chronic kidney disease, at least in individuals with highly dysfunctional ABCG2. This new finding highlights the potential importance of ABCG2 in the pathogenesis of hyperuricemia-induced kidney injury.

Keywords: ABCG2; ABCG2 function; eGFR slope; estimated glomerular filtration rate (eGFR); genetic risk factor; hyperuricemia; kidney disease progression; kidney function; null mutation; risk allele; serum uric acid (SUA); urate.