Association between Irisin and Cardiovascular Structure and Function in Patients with Advanced CKD

Background: Emerging evidence suggests that irisin, a myokine released from muscle during exercise, could exert cardiovascular (CV) protective effects. Circulating irisin is reduced as CKD progresses, and low irisin has been associated with increased risk of vascular calcification and CV mortality in patients on hemodialysis. However, to-date no studies have comprehensively studied its role in regulating CV structure and function in advanced CKD. Methods: We performed a cross-sectional analysis of 149 patients from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) cohort. All patients underwent cardiopulmonary exercise testing to assess CV functional capacity, echocardiography, and applanation tonometry. Patients were stratified by sex (M/F) and dialysis status (pre-dialysis (P), dialysis (D)) (n=16 P/F, n=41 D/F, n=23 M/P, n=69 M/D). Wilcoxon rank-sum tests were performed to assess differences in irisin levels. Multiple linear regression models were performed to examine associations between irisin and outcomes. Plasma irisin (ng/mL) was assessed via ELISA (Phoenix Pharmaceuticals, EK-067-29). Results: The mean age of the dialysis group was higher than the pre-dialysis group among males but not females (M: 50.8±13.9, p=0.0055, vs F: 41.3±13.7 yr, p=0.3). Additionally, there was no difference in BMI among all strata groups (p>0.05). Interestingly, irisin was higher in male dialysis compared to pre-dialysis patients (n=92, 8.8 vs 5.4 ng/mL, p=0.0003) but not in females (n=57, 8.3 vs 8.6 ng/mL, p=0.67). Multiple linear regression demonstrated that plasma irisin was not associated with VO2Max, left ventricular mass index, pulse pressure or augmentation index after adjusting for age, sex, BMI, dialysis status and phosphate levels. However, irisin concentration was negatively associated with maximum workload after the same adjustment (β=-1.8, p=0.04). Conclusion: This study suggests that irisin is dysregulated in kidney failure and may target the musculoskeletal system, rather than CV structure in advanced CKD patients. Additionally, the lack of a validated blood irisin assay is a current limitation in clinical studies. Future studies will assess the association of irisin with physical performance and quantitative musculoskeletal metrics (i.e. DXA) in CKD patients.