The interplay between cell-free DNA, hepcidin, and interleukin-6 in chronic kidney disease induced inflammation and progression to a hemodialysis dependent state.

Abstract

Inflammation drives chronic kidney disease (CKD) progression to end-stage renal disease (ESRD). Cell-free DNA (cfDNA) release is linked to systemic inflammation. Pro-inflammatory interleukin-6 (IL-6) is believed to induce hepcidin, the master regulator of iron metabolism. This study attempts to assess the link between cfDNA, IL-6, and hepcidin in CKD induced inflammation and evaluate their usefulness as indicators for progression. This study included 90 participants, divided into three equal groups. Group 1 comprised non-dialysis dependent CKD (ND-CKD) patients (stages IV and V); Group 2 comprised hemodialysis dependent ESRD (HD-ESRD) patients; and Group 3 comprised study normal controls. cfDNA concentration was determined using the real-time quantitative polymerase chain reaction (RT-qPCR). Serum hepcidin and IL-6 were assessed using enzyme-linked immunosorbent assay (ELISA) kits. The HD-ESRD group showed significant up-regulation of cfDNA, IL-6, and hepcidin compared to the ND-CKD group (p =0.008, p < 0.001, and p < 0.001, respectively) and to the control group (p =0.007, p < 0.001, and p < 0.001, respectively). The ND-CKD group showed no significant up-regulation in cfDNA compared to the control group. cfDNA was positively correlated with IL-6, hepcidin, and carotid intima-media thickness (CIMT). IL-6 had the highest discriminative power to detect CKD progression [area under the curve (AUC) of 0.84, 83% sensitivity (SN) and 73% specificity (SP)], followed by hepcidin [AUC 0.77, SN = 80%, and SP = 63%] and cfDNA [AUC 0.67, SN = 70%, and SP = 50%]. Logistic regression analysis revealed that up-regulated IL-6 and hepcidin were independent predictors of HD-ESRD progression, (odds ratio = 1.005 and 1.006, respectively). In conclusion, cfDNA was associated with IL-6 and hepcidin in CKD. Up-regulated IL-6 and hepcidin can serve as predictors of HD-ESRD progression. cfDNA was associated with CIMT in renal patients. IL-6 and hepcidin up-regulations may act as predictors of HD-ESRD progression.