Association between Systemic Inflammation and Worsening Renal Function in Cardiovascular-Kidney-Metabolic Syndrome

Introduction: As a concept recently proposed by the American Heart Association (AHA), cardiovascular-kidney-metabolic (CKM) syndrome is characterized by the interplay of cardiovascular, renal, and metabolic dysfunctions. However previous studies constantly focused on the cardiovascular outcomes, and there is scarce evidence addressing the association between chronic systemic inflammation and long-term changes in kidney function in the progression of CKM syndrome. Objective: This study aimed to investigate the association between the systemic inflammation and worsening renal function (WRF) in individuals with CKM syndrome. Methods: A cohort of 39944 outpatients with regular follow-up visits at Fuqing City Hospital from 2014 to 2021 was analyzed. WRF was defined as an absolute increase in serum creatinine (SCr) of ≥26.5 μmol/l (≥0.3 mg/dl) with a relative increase of ≥25% from baseline during the first year of follow-up. Three logistic regression models were constructed to evaluate the associations between systemic immune inflammation index (SII), systemic inflammatory response Index (SIRI) and WRF. Restricted cubic spline (RCS) regression was utilized to illustrate the relationship between SII, SIRI, and WRF. Additionally, we explored this correlation through segmented linear regression as part of our threshold analysis. Results: A total of 10361 individuals (25.9%) experienced WRF within the first year. Higher levels of SII and SIRI were significantly associated with increased odds of WRF across all CKM stages. After adjusting for multiple conventional variables SII remained an independent predictor for WRF(OR: 1.298, 95%CI 1.181-1.427, P < 0.001). Similarly, SIRI also demonstrated a significant positive correlation with WRF (OR: 1.026, 95% 1.021-1.030, P < 0.001). The RCS analysis also revealed a dose-response relationship, indicating that higher quartiles of SII and SIRI correlating with greater odds of WRF. Further analysis revealed significant interactions between SII, SIRI and CKM stages, particularly at stages 4 (P < 0.001 for both). Subgroup analysis suggested that this association between SII, SIRI and WRF was more prominent in the early stage of CKM. The threshold effect analysis demonstrated that for ln transformed SII, a threshold of above 5.565 indicated significant correlation with WRF (OR:1.277), while for SIRI, the threshold of 2.34 showed a strong correlation below it (OR:1.330). Conclusion: Both SII and SIRI were associated with the risk of WRF in individuals with CKM. This association seemed more prominent in the early stage of CKM.