Leukocyte telomere length mediates the association between SIRI and CKD: insights from NHANES 1999–2002

Chronic kidney disease (CKD) is closely linked to systemic inflammation and accelerated cellular aging. However, the role of the systemic inflammation response index (SIRI) and leukocyte telomere length (LTL), a biomarker of cellular aging, in the development and progression of CKD remain incompletely elucidated. We analyzed cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) (1999–2002), which included 3805 individuals. Participants were divided into subgroups: (1) CKD versus non-CKD and (2) SIRI quartiles (Q1-Q4). SIRI was calculated as (monocytes × neutrophils)/lymphocytes. CKD was defined by urinary albumin to creatinine ratio (UACR) ≥30 mg/g or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m². LTL was quantified by quantitative polymerase chain reaction (qPCR). Weighted logistic regression models used to assess the associations of SIRI, LTL, and CKD, adjusting for demographics, socioeconomic factors, lifestyle, and comorbidities. Mediation analysis was performed to quantify the indirect effect of SIRI on CKD via LTL shortening. Participants with CKD exhibited significantly higher SIRI values (p < 0.001) and shorter LTL (p < 0.001) compared those without CKD. In fully adjusted models, higher SIRI quartiles showed a dose-response relationship with CKD risk: Q3 (OR = 1.442, p = 0.046) and Q4 (OR = 2.165, p < 0.001). Conversely, longer LTL was inversely associated with CKD risk across quartiles: Q2 (OR = 0.681, p = 0.047), Q3 (OR = 0.567, p = 0.015), and Q4 (OR = 0.445, p = 0.004). Furthermore, higher SIRI quartiles showed significant inverse associations with LTL compared to Q1: Q3 (OR = 0.955, p = 0.040) and Q4 (OR = 0.944, p = 0.007). Mediation analysis showed that LTL mediated 7.8% (95% CI: 4.12%, 15.63%) of the total effect of SIRI on CKD (indirect effect: OR = 1.002, p < 0.001), while the direct effect remained statistically significant (OR = 1.026, p < 0.001). Sensitivity analyses verified the robustness of the results. Systemic inflammation, as quantified by the SIRI, has a significant impact on CKD risk through its contribution to LTL attrition. This process highlights the complex interplay between systemic inflammation and biological aging in the pathophysiology of CKD.