WCN26-5628 Systemic inflammatory profiles prognose long-term progression and mortality in late-stage chronic kidney disease

Introduction: Chronic kidney disease (CKD) is a global health burden and CKD stage G3 is the most prevalent and heterogeneous in elderly patients, frequently remaining stable over time.Actual risk stratification based on eGFR and albuminuria (uACR) provides limited prognostic precision.Systemic inflammation and cellular stress pathways are key regulators of cytokine release and metabolic adaptation in CKD.Endoplasmic reticulum (ER) stress induces transcriptional activation and upregulates cytokines.We aimed to investigate plasma and urinary cytokine profiles to identify inflammatory phenotypes associated with disease progression and long-term outcomes in CKD G3, with and without diabetes.Methods: A prospective multicenter observational study in 25 nephrology units in Spain.A total of 462 CKD G3 patients were enrolled from 2012 to 2015.Inclusion criteria were the age older than 18 years, eGFR 30-59 mL/min/1.73m 2 , and albuminuria category A1 to A3. Seventeen plasma and ten urinary cytokines were quantified using automated immunoassay platform (HISCL-5000/800, Sysmex).Patients were followed for 36 months with repeat sampling and for 10 yearclinical outcomes including kidney failure with kidney replacement therapy (KRT) or death.Cytokine data were analyzed using nonparametric statistics, multivariable regression adjusted for age and sex, and unsupervised hierarchical clustering to define inflammatory phenotypes.Results: Median age was 68 years; 39% had diabetes.Baseline median eGFR was 42.8 mL/min/1.73m 2 and uACR 42.7 mg/g.Plasma levels of 15 cytokines and 6 urinary cytokines differed between patients with CKD and healthy controls.Among all cytokines, plasma IL-8, IL-22, TNF-, and GDF-15 showed significant associations with short-term changes in uACR and eGFR.Plasma GDF-15 was independently associated with 10-year mortality and KRT after age-sex adjustment.Cluster analysis of plasma cytokine profiles identified six inflammatory phenotypes.Clusters 1 and 2 (intermediate IL-8 and IL-22 activity) showed slower CKD progression.Cluster 3 (High TNF-, GDF-15, IL-22) showed older age, accelerated eGFR decline, higher albuminuria, and the highest 10-year KRT rate (33%).Cluster 4 (All High) showed the highest uACR, fastest progression, and 10-year mortality of 77.8%.Cluster 5 (High GDF-15) is a rare cluster with 80% mortality.Cluster 6 (All Low) showed younger age, preserved eGFR, lower uACR, and the lowest risk of adverse outcomes.At 10 years, 20.6% of patients required KRT, and 34.4% died; the combined endpoint occurred in 47.8%.Cytokine clusters correlated with KDIGO risk categories, cardiovascular hospitalizations, and both mortality and KRT (p<0.001).Cluster transitions during 36 months revealed increasing systemic inflammation over time, particularly from low-to high-TNF-a/GDF-15 clusters. Conclusion:In patients with CKD G3, plasma cytokine signatures reflect systemic inflammatory phenotypes and link to kidney function decline, uACR progression, and 10-year outcomes.High GDF15 and TNF- could identify a high-risk group for mortality and KRT, while low-cytokine clusters represent slow progressors.These findings suggest that GDF15 and TNF- contribute to the systemic inflammation driving CKD progression.This may guide future trials exploring anti-inflammatory and ER stress-modulating therapies for kidney protection.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.