Myeloid inflammation thresholds stratify mortality risk in early-stage cardiovascular-kidney-metabolic syndrome: MLR-driven findings from NHANES.

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome is a major public health concern associated with increased mortality. Inflammation plays a critical role in CKM progression and outcomes. This study investigates the relationship between inflammatory indices and mortality risk in CKM patients.

METHODS: A comprehensive analysis of data from 26,265 participants in the National Health and Nutrition Examination Survey (NHANES) database (2007-2016) with CKM syndrome stages 0-4 was conducted. The primary outcomes of the study were all-cause and cardiovascular mortality. The inflammatory indices encompassed the systemic inflammation response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), aggregate index of systemic inflammation (AISI), and neutrophil-to-albumin ratio (NAR). Multivariable Cox models, adjusted for demographic and clinical confounders, were employed to examine nonlinearity, alongside restricted cubic splines and threshold analyses. The present study sought to compare the prognostic accuracy of the time-dependent ROC (Receiver Operating Characteristic) at 93 months.

RESULTS: During a median follow-up of 93.4 months, 2,292 subjects experienced all-cause mortality and 701 experienced cardiovascular deaths. In the adjusted models, elevated SIRI (all-cause HR 1.11, 95% CI 1.06-1.15; cardiovascular HR 1.18, 1.10-1.27), NLR (all-cause HR 1.08, 1.05-1.12; cardiovascular HR 1.11, 1.05-1.17) and MLR (all-cause HR 2.27, 1.71-3.01; cardiovascular HR 3.37, 2.09-5.44) were independently associated with mortality (all p < 0.0001). Dose-response analyses revealed nonlinear J-shaped relationships: MLR showed marked risk above 0.19 (HR 2.59), NLR risk was greatest below 3 (HR 1.14), and SIRI thresholds differed for all-cause (> 1.74, HR 1.09) versus cardiovascular (> 0.38, HR 1.17) outcomes. At 93 months, MLR demonstrated the highest discriminatory ability (AUC 0.630; C-index 0.667; p < 0.001), outperforming SIRI (AUC 0.611) and NLR (AUC 0.602). PLR, AISI, SII and NAR showed limited predictive value due to imbalanced sensitivity-specificity. The impact of age and the early stages of CKD on the modification of associations was investigated.

CONCLUSION: Systemic inflammatory indices demonstrated nonlinear, J-shaped associations with mortality in CKM syndrome, with the MLR showing the strongest association across disease trajectories. MLR, NLR, and SIRI were identified as potential risk indicators, with stronger associations observed in younger patients and those with early-stage CKM syndrome.

HIGHLIGHTS: Systemic inflammatory markers (SIRI, NLR, MLR) were significantly associated with increased mortality risk in CKM syndrome. Most inflammation indices exhibited nonlinear, J-shaped associations with mortality. Nonlinear threshold analyses identified specific risk inflection points for SIRI, NLR, and MLR. These associations were stronger in younger patients (≤ 60 years) and those with early CKM stages (1-2).