This study investigates the association between the systemic inflammation response index (SIRI) and chronic kidney disease (CKD) using data from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2020. The study found a positive correlation between SIRI and CKD, with a nonlinear relationship, suggesting that SIRI levels above 2.04 are associated with a higher risk of CKD. Additionally, SIRI was positively correlated with albuminuria and low estimated glomerular filtration rate (eGFR), with nonlinear relationships at breakpoints of 2.18 and 1.85, respectively. Other inflammatory biomarkers such as the systemic immune-inflammation index (SII), neutrophil/high-density lipoprotein ratio (NHR), monocyte/high-density lipoprotein ratio (MHR), platelet/high-density lipoprotein ratio (PHR), and lymphocyte/high-density lipoprotein ratio (LHR) were also found to be positively correlated with CKD, albuminuria, and low eGFR. However, SIRI demonstrated superior predictive accuracy and discriminative ability compared to these other biomarkers. The study concludes that elevated SIRI levels may be a significant indicator of kidney health risks in American adults.This study investigates the association between the systemic inflammation response index (SIRI) and chronic kidney disease (CKD) using data from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2020. The study found a positive correlation between SIRI and CKD, with a nonlinear relationship, suggesting that SIRI levels above 2.04 are associated with a higher risk of CKD. Additionally, SIRI was positively correlated with albuminuria and low estimated glomerular filtration rate (eGFR), with nonlinear relationships at breakpoints of 2.18 and 1.85, respectively. Other inflammatory biomarkers such as the systemic immune-inflammation index (SII), neutrophil/high-density lipoprotein ratio (NHR), monocyte/high-density lipoprotein ratio (MHR), platelet/high-density lipoprotein ratio (PHR), and lymphocyte/high-density lipoprotein ratio (LHR) were also found to be positively correlated with CKD, albuminuria, and low eGFR. However, SIRI demonstrated superior predictive accuracy and discriminative ability compared to these other biomarkers. The study concludes that elevated SIRI levels may be a significant indicator of kidney health risks in American adults.