#3196 Inflammatory cytokine clusters are associated with adverse outcomes in patients with CKD

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Abstract Background and Aims Chronic kidney disease (CKD) is one of the fastest growing global causes of death, characterized by a gradual loss of renal function over time leading to kidney failure. Early detection of progression and treatment are key for CKD management. The rate of estimated glomerular filtration rate (eGFR) decline can vary substantially among CKD patients, ranging from stable levels to relatively rapid reduction in kidney function. Cross-sectional observational studies demonstrate an association between chronic inflammation, evidenced by elevated levels of circulating inflammatory cytokines, and lower eGFR. Emerging experimental evidence suggests that inflammatory cytokines may directly contribute to glomerular and tubular injury, promote fibrosis, and exacerbate vascular damage, collectively compromising nephron integrity function. Therefore, it is hypothesized that the inflammatory status plays a critical role in the progression of kidney damage. In this study, we examined the relationship between plasma and urinary cytokine levels and the long-term prognosis of progression in CKD. Method This study included 165 CKD patients from the original PROGRESER cohort. Plasma and urine cytokine levels were measured at baseline, 18 and 36 months using the Sysmex fully automated immunoassay analysers (HISCL-5000 and HISCL-800). Three-year follow-up clinical parameters were retrieved from the original PROGRESER case report forms, and additional 10-year follow-up data were collected from participating centers. CKD patients were categorized into three groups—non-diabetic (non-DM, N = 100), type 1 diabetes (T1D, N = 5), and type 2 diabetes (T2D, N = 60)—and compared to healthy controls (N = 30). Disease progression was calculated by dividing changes in clinical outcomes by the number of observation days. Cytokines with significant correlations to clinical parameters (eGFR, urine albumin-to-creatinine ratio -UACR-, HbA1c) were pre-selected through univariate and multivariate analyses. Multiple logistic regression analysis between KDIGO and other risk categories identified three cytokines for cluster analysis. Descriptive data were reported as medians with interquartile ranges (IQR) due to non-normal distributions. Statistical tests, including Fisher’s exact test, Steel-Dwass test, and Mann–Whitney U test, were conducted using R software (version 4.0.3). Two-tailed p-values < 0.05 were considered statistically significant. Results The median age was 70 years for diabetic CKD patients and 66 years for non-DM CKD patients, UACR 59.7 mg/g and 31.3 mg/g, respectively. All participants had CKD G3–G5. Plasma levels of IL-5, IL-6, IL-8, IL-17, IL-18, PROTEIN-A*, CXCL9, PROTEIN-B, BAFF, and GDF-15 were significantly elevated, whereas IL-10, CCL5, and TWEAK were reduced in non-diabetic and diabetic CKD compared to healthy controls (P < .05). Urinary PROTEIN-A was also significantly elevated (P < .05). Cluster analysis based on IL-8, PROTEIN-B, and GDF-15 identified clusters with distinct inflammatory profiles. Clusters 3 and 4, characterized by higher inflammation, had a greater proportion of patients classified as Very High Risk by KDIGO criteria and a higher prevalence of diabetic kidney disease compared to Cluster 5, which exhibited lower inflammation. Cluster 3 also demonstrated a larger increase in UACR and a higher number of all-cause deaths (P < 0.0001), primarily due to cardiovascular causes. Conclusion Inflammatory cytokine clusters are strongly associated with CKD progression and adverse outcomes. Patients in high-inflammation clusters (IL-8, PROTEIN-B, GDF-15) had increased KDIGO Very High-Risk classification, greater UACR progression, and higher mortality, mainly due to cardiovascular causes. These findings highlight the prognostic value of cytokine profiling in CKD management. *Names withheld for intellectual property reasons.

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