A Novel Insight into the Interplay between Serum Uric Acid and Blood Parameters: Unveiling a Complex Relationship

Serum uric acid (SUA), the end product of purine metabolism, is widely used in clinical and population health settings and is implicated in gout, cardiometabolic disorders, and kidney disease. Although SUA has been linked to routine hematological indices and inflammatory markers, population-level characterization of these relationships, especially potential non-linear patterns, and the extent to which routinely used renal biomarkers explain these associations remain insufficiently defined.

We conducted a cross-sectional analysis of 12,948 adults from NHANES 2015-March 2020 (pre-pandemic). Hematological parameters included red blood cell count (RBC), hemoglobin (HGB), white blood cell count (WBC), platelet count (PLT), C-reactive protein (CRP), and the hemoglobin-to-red cell distribution width ratio (HGB/RDW). Serum creatinine (Scr) and blood urea nitrogen (BUN) were evaluated as renal biomarkers potentially accounting for hematological-SUA associations. Survey-weighted generalized linear models (GLMs) estimated associations across nested adjustment sets; restricted cubic splines (RCS) assessed non-linearity; and mediation analyses decomposed associations into indirect (via Scr or BUN) and direct components; because available mediation methods do not fully incorporate the NHANES complex survey design, mediation results were conducted without sampling weights and interpreted as exploratory association decompositions.

In fully adjusted survey-weighted models, RBC showed the most prominent positive association with SUA, while WBC and CRP exhibited smaller but statistically detectable positive associations; PLT showed no statistically significant association with SUA in the fully adjusted model. RCS analyses suggested non-linear exposure-response patterns for several indices: RBC demonstrated an U-shaped relationship with SUA, and HGB/ RDW showed a non-linear pattern with peak SUA at intermediate levels. For WBC and CRP, spline curves were consistent with a saturating pattern (steeper increases at lower levels with plateauing at higher levels). Mediation analyses indicated that Scr and BUN accounted for a variable proportion of hematological-SUA associations, and for some indices the indirect and direct components operated in opposite directions, consistent with a suppression-type decomposition.

SUA was found to be correlated with a set of hematological and inflammatory markers measured routinely in a nationally representative sample of adults in the U.S., with RBC and a non-linear relationship between HGB/RDW standing out as notable features. Renal biomarkers (Scr and BUN) statistically explained part of these associations, supporting an integrated interpretation of blood and kidney markers when characterizing SUA-related risk profiles. Longitudinal studies are needed to evaluate temporal ordering and causal mechanisms.