Zinc deficiency as a contributor to acute kidney injury in patients with chronic kidney disease: a propensity score-matched retrospective analysis

Abstract

Background: Acute kidney injury (AKI) is a frequent and serious complication in patients with chronic kidney disease (CKD) that often leads to poor clinical outcomes. Despite the biological plausibility of linking zinc deficiency (ZD) to increased AKI susceptibility, large-scale evidence evaluating this association in the CKD population remains scarce.

Methods: This retrospective cohort study utilized the TriNetX Analytics Network Platform to identify patients aged ≥18 years with pre-existing CKD who underwent serum zinc testing between January 2010 and December 2023. Patients were categorized into zinc deficiency (ZD: <70 μg/dl) and control groups (70-120 μg/dl). After applying the exclusion criteria and 1:1 propensity score matching for demographics, comorbidities, laboratory parameters, and medications, we analyzed 5,619 patients per group. The primary outcome was new-onset AKI at the 12-month follow-up, with secondary outcomes including risk of mortality, end-stage renal disease (ESRD), intensive care unit (ICU) admission, and major cardiac adverse events (MCAEs).

Results: At 12 months, zinc-deficient patients experienced significantly higher risks of AKI [19.3 vs. 14.9%; hazard ratio (HR): 1.37, 95% confidence interval (CI): 1.25-1.50, P < 0.001], mortality (9.0 vs. 4.8%; HR 1.95, 95% CI 1.68-2.26, P < 0.001), ESRD progression (1.9 vs. 1.4%; HR 1.40, 95% CI 1.04-1.88, P = 0.025), and ICU admissions (8.7 vs. 5.8%; HR 1.56, 95% CI 1.35-1.79, P < 0.001). The effects were stronger at 6 months than at 12 months, suggesting rapid manifestation. Notably, these zinc-specific effects persisted even after excluding patients who developed malnutrition, reinforcing that the observed associations were attributable to zinc deficiency rather than general nutritional status. Subgroup analyses demonstrated consistent findings across diverse patient characteristics.

Conclusions: Baseline zinc deficiency is an independent, modifiable risk factor for AKI development and mortality in patients with CKD. These findings support routine zinc status assessments and targeted supplementation strategies in CKD management protocols. However, the observational design and single-point zinc measurements limit the causal inferences. Prospective randomized controlled trials are needed to determine whether zinc supplementation can prevent AKI and improve outcomes in patients with CKD.

Keywords: kidney function decline; nutritional assessment; risk factor; trace elements; zinc level.

Figure 1

Patient selection flowchart from the TriNetX database. The flowchart illustrates the systematic exclusion process applied to identify eligible patients with zinc deficiency (ZD) and zinc sufficiency (control group). HCOs, Healthcare Organizations.

Figure 2

Propensity score density distributions before and after matching. The left panel shows imbalanced distributions between the zinc deficiency (Cohort 1) and control groups (Cohort 2) before matching. The right panel demonstrates improved alignment and covariate balance after 1:1 matching with a 0.1 standard deviation caliper.

Figure 3

Subgroup analysis of the association between zinc deficiency and risk of acute kidney injury (AKI). Hazard ratios (HRs) and 95% confidence intervals are shown for each subgroup. The interaction P-values indicate no significant effect modification across sex, age, anemia, hypertension, diabetes mellitus (DM), or obesity status.