Uric Acid and the Risks of Kidney Failure and Death in Individuals With CKD

Abstract

Background: Serum uric acid concentrations increase in chronic kidney disease (CKD) and may lead to tubular injury, endothelial dysfunction, oxidative stress, and intrarenal inflammation. Whether uric acid concentrations are associated with kidney failure and death in CKD is unknown.

Study design: Prospective observational cohort study.

Settings & participants: 3,885 individuals with CKD stages 2 to 4 enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and September 2008 and followed up through March 2013.

Predictor: Baseline uric acid concentrations.

Outcomes: Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality.

Results: During a median follow-up of 7.9 years, 885 participants progressed to kidney failure and 789 participants died. After adjustment for demographic, cardiovascular, and kidney-specific covariates, higher uric acid concentrations were independently associated with risk for kidney failure in participants with estimated glomerular filtration rates (eGFRs) ≥ 45mL/min/1.73m² (adjusted HR per 1-standard deviation greater baseline uric acid, 1.40; 95% CI, 1.12-1.75), but not in those with eGFRs<30mL/min/1.73m². There was a nominally higher HR in participants with eGFRs of 30 to 44mL/min/1.73m² (adjusted HR, 1.13; 95% CI, 0.99-1.29), but this did not reach statistical significance. The relationship between uric acid concentration and all-cause mortality was J-shaped (P=0.007).

Limitations: Potential residual confounding through unavailable confounders; lack of follow-up measurements to adjust for changes in uric acid concentrations over time.

Conclusions: Uric acid concentration is an independent risk factor for kidney failure in earlier stages of CKD and has a J-shaped relationship with all-cause mortality in CKD. Adequately powered randomized placebo-controlled trials in CKD are needed to test whether urate lowering may prove to be an effective approach to prevent complications and progression of CKD.

Keywords: CKD progression; Chronic Renal Insufficiency Cohort (CRIC); Uric acid; chronic kidney disease (CKD); death; eGFR decline; end-stage renal disease (ESRD); hyperuricemia; kidney failure.

Fig. 1. Primary Outcome Event Rates by Uric Acid Quartiles

Event rates (per 1000 person-years) of participants reaching the outcomes by uric acid quartile.

Fig. 2. Uric Acid and Risk of Kidney Failure by Baseline Kidney Function

Multivariable adjusted hazard ratios of kidney failure per 1SD greater baseline uric acid in all participants and stratified by baseline eGFR. See Model 4 in Table 2 for adjusted covariates. Adjusted HRs are as follows: total cohort, 1.01 (95% CI, 0.93–1.10); eGFR ≥45 ml/min/1.73 m2, 1.40 (95% CI, 1.12–1.75); eGFR of 30–44 ml/min/1.73 m2, 1.13 (95% CI, 0.99–1.29); eGFR < 30 ml/min/1.73 m2, 0.82 (95% CI, 0.72–0.94).

Fig. 3. Association between Uric Acid and All-Cause Mortality

Restricted cubic spline model reflecting fully adjusted model for covariates described in Model 4 of Table 2 (P for non-linear association = 0.007). Mean uric acid (7.4 mg/dl) is the reference.