Platelet-Dependent Inflammatory Dysregulation in Patients with Stages 4 or 5 Chronic Kidney Disease: A Mechanistic Clinical Study

Key Points Patients with CKD have a reduced platelet count, higher platelet volume, reduced platelet-leukocyte interactions, and higher nonclassic monocytes. Platelet-derived cytokines are one of the central cytokines in correlation analysis of 45-cytokine panel in patients with stages 4 or 5 CKD. Antiplatelet drugs had multifaceted effects on thromboinflammation, suggesting platelet-dependent and -independent inflammation in CKD. Visual Abstract Background Chronic kidney disease (CKD) is characterized by dysregulated inflammation that worsens with CKD severity. The role of platelets in modulating inflammation in stage 4 or 5 CKD remains unexplored. We investigated whether there are changes in platelet-derived thromboinflammatory markers in CKD with dual antiplatelet therapy (DAPT; aspirin 81 mg/d plus P2Y12 inhibitor). Methods In a mechanistic clinical trial, we compared platelet activation markers (aggregation and surface receptor expression), circulating platelet-leukocyte aggregates, leukocyte composition (monocyte subtypes and CD11b surface expression), and plasma cytokine profile (45 analytes) of non-CKD controls (n=26) and CKD outpatients (n=48) with a glomerular filtration rate (GFR) <30 ml/min per 1.73 m2 on 2 weeks of DAPT. Results Patients with CKD demonstrated a reduced mean platelet count, elevated mean platelet volume, reduced platelet-leukocyte aggregates, reduced platelet-bound monocytes, higher total non-classic monocytes in the circulation, and higher levels of IL-1RA, VEGF, and fractalkine (all P<0.05). There were no differences in platelet activation markers between CKD and controls. Although DAPT reduced platelet aggregation in both groups, it had multifaceted effects on thromboinflammatory markers in CKD, including a reduction in PDGF levels in all CKD individuals, reductions in IL-1β and TNF-α levels in select CKD individuals, and no change in a number of other cytokines. Significant positive correlations existed for baseline IL-1β, PDGF, and TNF-α levels with older age, and for baseline TNF-α levels with presence of diabetes mellitus and worse albuminuria. Mean change in IL-1β and PDGF levels on DAPT positively correlated with younger age, mean change in TNF-α levels with higher GFR, and mean changes in PDGF, and TRAIL levels correlated with worse albuminuria. Minimum spanning trees plot of cytokines showed platelet-derived CD40L had a large reduction in weight factor after DAPT in CKD. Additionally, platelet-derived IL-1β and PDGF were tightly correlated with other cytokines, with IL-1β as the hub cytokine. Conclusions Attenuated interactions between platelets and leukocytes in the CKD state coincided with no change in platelet activation status, an altered differentiation state of monocytes, and heightened inflammatory markers. Platelet-derived cytokines were one of the central cytokines in patients with CKD that were tightly correlated with others. DAPT had multifaceted effects on thromboinflammation, suggesting that there is platelet-dependent and -independent inflammation in stage 4 or 5 CKD.