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 (Factores de PROGRESion en Enfermedad Renal) 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 interleukin (IL)-8 levels were inversely associated with uACR slopes, while IL-22, tumour necrosis factor (TNF)-? and Growth Differentiation Factor 15 (GDF-15) levels showed positive correlations with uACR progression. Additionally, plasma TNF-? and GDF-15 were associated with KRT and/or death with 10 years.Cluster analysis of plasma IL-8, IL-22, TNF-? and GDF-15 identified six distinct patient clusters. Clusters 3 (elevated levels of IL-22, TNF-?, GDF-15), 4 (elevated levels of all four cytokines) and the uncommon Cluster 5 (high GDF-15 only) were associated with worse kidney, cardiovascular and survival outcomes, while Cluster 6 (low cytokine levels) represented patients with slower disease progression and the 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.