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Systemic inflammatory profiles are associated with long-term kidney failure and patient mortality in chronic kidney
Alberto Martínez-Castelao1,2, Takehiro Hasegawa3, Beatriz Fernández-Fernández2,4,5
1Nefrología, Hospital Universitari de Bellvitge, Hospitalet, Barcelona, Spain.
Insights
Chronic kidney disease (CKD) progression can be predicted by inflammatory cytokine profiles. Specific cytokine clusters in CKD patients indicate higher risks for kidney failure, cardiovascular disease, and mortality.
Area of Science:
- Nephrology
- Immunology
- Biomarkers
Background:
- Chronic kidney disease (CKD) is often linked to systemic inflammation, but the precise role of inflammatory cytokines in CKD progression is not fully understood.
- Understanding these relationships is crucial for predicting disease trajectory and patient outcomes.
Purpose of the Study:
- To investigate the association between plasma and urinary inflammatory cytokine profiles and the progression of CKD in patients with stage G3 CKD.
- To identify specific cytokine patterns that correlate with kidney function decline, cardiovascular events, and mortality.
Main Methods:
- The PROGRESER study prospectively followed 165 patients with CKD stage G3, measuring 17 plasma and 10 urinary cytokines at multiple time points.
- Unsupervised cluster analysis was used to group patients based on cytokine levels.
- Associations between cytokine levels, patient clusters, and clinical outcomes (eGFR, uACR, kidney replacement therapy, cardiovascular hospitalization, death) were assessed over a 10-year follow-up.
Main Results:
- Plasma levels of several cytokines, including IL-8, IL-22, TNF-α, and GDF-15, differed between CKD patients and healthy controls.
- Elevated levels of IL-22, TNF-α, and GDF-15 were associated with poorer kidney outcomes (e.g., increased uACR progression) and worse long-term survival.
- Cluster analysis revealed six distinct patient groups; clusters with higher levels of these inflammatory cytokines showed significantly worse kidney, cardiovascular, and survival outcomes.
Conclusions:
- Systemic inflammation, as reflected by cytokine profiles, can effectively stratify CKD G3 patients.
- Specific inflammatory cytokine clusters are predictive of accelerated CKD progression, increased cardiovascular risk, and higher mortality.
- These findings highlight the potential of cytokine profiling for risk stratification and personalized management in CKD.
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)-α and Growth Differentiation Factor 15 (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 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.
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