Systemic inflammatory profiles are associated with long-term kidney failure and patient mortality in chronic kidney disease

Abstract Background Chronic kidney disease (CKD) is frequently associated with systemic inflammation. However, the relationship between inflammatory cytokines and CKD progression remains incompletely understood. Methods The PROGRESER study was a multicentre, prospective observational cohort that included patients with CKD stage G3. A total of 17 plasma and 10 urinary inflammatory cytokines were measured in 165 participants, at baseline, 18 months, and 36 months using a fully automated HISCL immune analyser. Unsupervised cluster analysis identified six distinct patient clusters. Associations between cytokine levels and kidney outcomes [estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (uACR), KDIGO risk scores, kidney replacement therapy (KRT)], cardiovascular outcomes (cardiovascular hospitalization) and death was assessed during a follow-up of up to 10 years. The primary outcome was a combination of KRT or death. Results Plasma levels of 15 cytokines and 6 urinary cytokines differed between patients with CKD and 30 healthy controls. Of these, plasma IL-8 levels were inversely associated with uACR slopes, while IL-22, TNF-α, and GDF-15 levels showed positive correlations with uACR progression. Additionally, plasma TNF-α and GDF-15 were associated with KRT and/or death with 10 years. Cluster analysis of plasma IL-8, IL-22, TNF-α, and GDF-15 identified six distinct patient clusters. Clusters 3 (elevated levels of IL-22, TNF-α, GDF-15), 4 (elevated levels of all four cytokines) and the uncommon cluster 5 (high GDF15 only) were associated with worse kidney, cardiovascular and survival outcomes, while cluster 6 (low cytokine levels), represented patients with slower disease progression and best long-term outcomes. Over time, patients frequently transitioned to more severe clusters. Conclusion In CKD G3 patients, systemic inflammation can be stratified using cytokine profiles. Specific cytokine clusters are linked to faster progression of CKD and cardiovascular disease, and to worse long-term outcomes including kidney failure and mortality.