Platelet Transcriptome Analysis in CKD Provides Insight into Cardiovascular Events

Background: Platelet dysfunction is common in patients with CKD and contributes to hemorrhagic tendencies as well as CVD, but to our knowledge effects of CKD on the platelet transcriptome have not been analyzed. Methods: We compared the platelet transcriptome from prospectively recruited patients with peripheral artery disease according to eGFR and CKD class: moderate CKD (eGFR of 30-<60 mL/min/1.73m2), severe CKD (eGFR of < 30 mL/min/1.73,2), or chronic dialysis. Results were adjusted for age, sex, ethnicity and race. Results: 54 participants had CKD (28% male, mean age 72, and 12% Black) and 81 had preserved kidney function (62% male, mean age 69, and 15% Black). After adjusting for age, sex, race, ethnicity, and multiple comparisons, we identified 17 differentially expressed genes in moderate CKD (13 upregulated, 4 downregulated), & 344 in severe CKD (188 upregulated, 156 downregulated), and 560 in chronic dialysis (274 upregulated , 286 downregulated) compared with preserved kidney function. We defined a transcriptomic signature of 13 genes differentially expressed in CKD, and showed that this signature associated with CKD severity in a test cohort (N=40). This signature was correlated with epinephrine and ADP induced platelet aggregation and was significantly associated with mortality and major adverse cardiovascular events in adjusted analyses. In additional analyses multiple genes were significantly correlated with eGFR. Mitochondrial function and RNA function processes were particularly impacted (Figure) Conclusion: These findings demonstrate a unique platelet transcriptomic signature in CKD that is associated with future risk of cardiovascular events.