Abstract Background Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular (CV) and thrombotic events. Evidence suggests that complement activation contributes to thrombotic risk in patients with CKD, however the underlying mechanisms remain incompletely understood. Purpose Here, we investigated the role of complement proteins on cardiovascular outcomes in CKD. Methods Proteomic data from 44,856 UK Biobank participants were analyzed to assess correlations between complement proteins and estimated glomerular filtration rate (eGFR, CKD-EPI formula). The rate-limiting alternative pathway protein, complement factor D (CFD) showed the strongest correlation with eGFR (R = 0.36, p 0.000001) among all complement proteins. To examine the association between CFD and major adverse cardiovascular events (MACE) a cox proportional hazards model was used. In addition, CFD was validated experimentally by assessment of plasmin-induced clot lysis time to assess. Results After multivariable adjustment, CFD remained an independent predictor of MACE (HR 1.25, 95% CI 1.15–1.36, p 0.0001; Figure 1a). Patients with both high CFD levels (highest tertile) and eGFR 60 mL/min exhibited the highest risk of MACE (HR 1.82, 95% CI 1.51–2.18, p 0.0001; Figure 1b). Given the association between CFD and thrombotic outcomes, we experimentally assessed the impact of CFD on plasmin-induced clot lysis time, an established marker for thrombosis. Alternative pathway activation by Zymosan in CFD-depleted plasma increased clot lysis time by approximately 30%, which was further prolonged to 80% upon CFD reconstitution (p = 0.0075). Comparative experiments using plasma from hemodialysis (HD) patients (N = 10) and healthy controls (N = 10) demonstrated a significantly greater Zymosan-induced increase in clot lysis time in HD patients (141±45% vs. 249±78%, p 0.0001) that linked with elevated plasma CFD (0.71±0.14 µg/mL vs. 8.13±5.27 µg/mL, p = 0.003) and Fragment Bb levels (0.79±0.16 vs. 1.37±0.67, p = 0.0176). These findings suggest that CFD-mediated alternative pathway activation contributes to a procoagulant phenotype in CKD, particularly in advanced stages requiring hemodialysis. Conclusion This study identifies CFD as a novel biomarker linking complement system activation to thrombotic risk in CKD. Elevated CFD levels in CKD patients are associated with increased alternative pathway activity, impaired fibrinolysis, and heightened CV risk, particularly in those with reduced renal function. These findings underscore the potential for CFD as a therapeutic target to mitigate thrombotic complications in CKD and highlight the broader role of complement activation in CKD pathophysiology.
Berger et al. (Sat,) studied this question.