Association of Time-Updated Anion Gap With Risk of Kidney Failure in Advanced CKD: A Cohort Study

Abstract

Rationale & objective: High anion gap acidosis frequently develops in patients with advanced chronic kidney disease (CKD) and might be involved in kidney injury. Its impact on kidney outcomes, however, has not been well studied. We sought to examine the association between time-updated anion gap and the risk of kidney failure with replacement therapy (KFRT) among patients with advanced CKD.

Study design: Retrospective cohort study.

Setting & participants: 1,168 patients with CKD glomerular filtration rate categories 3b-5 (G3b-G5) who had available data on anion gap.

Exposure: High time-updated anion gap defined as values ≥ 9.2 (top 25th percentile).

Outcome: KFRT and death.

Analytical approach: Marginal structural models were fit to characterize the association between anion gap and study outcomes while accounting for potential time-dependent confounding.

Results: The mean baseline estimated glomerular filtration rate (eGFR) of the study participants was 28 mL/min/1.73 m². Over a median follow-up period of 3.1 years, 317 patients progressed to KFRT (7.5 per 100 patient-years), and 146 died (3.5 per 100 patient-years). In the marginal structural models, a high anion gap was associated with a higher rate of KFRT (HR, 3.04 [95% CI, 1.94-4.75]; P < 0.001). This association was stronger in patients with a baseline eGFR of <30 mL/min/1.73 m² (P for interaction = 0.05). High anion gap was also associated with a higher mortality rate (HR, 5.56 [95% CI, 2.95-10.5]; P < 0.001). Sensitivity analyses with different definitions of high anion gap showed similar results.

Limitations: Observational study design and selection bias due clinical indications for measuring anion gap.

Conclusions: Among patients with advanced CKD, high anion gap was associated with an increased risk of progression to KFRT and death.

Keywords: Acid-base disturbance; CKD progression; anion gap; chronic kidney disease (CKD); kidney failure with replacement therapy; marginal structural model (MSM); metabolic acidosis; mortality; uremic toxins.