JOURNAL OF MEDICINE CARE AND HEALTH REVIEW

Renal Functional Outcomes

Hemostatic and Biomarker Changes

Baseline platelet count, fibrinogen, D-dimer, prothrombin time (PT), and activated partial thromboplastin time (aPTT) were within expected ranges for this patient population. At 24 hours post-procedure:

• Platelet count decreased from 234 ± 51 to 220 ± 48 ×10³/µL (p = 0.04).
• Fibrinogen increased from 3.1 ± 0.7 to 3.6 ± 0.8 g/L (p < 0.001).
• D-dimer rose from 0.76 ± 0.32 to 1.15 ± 0.44 mg/L FEU (p < 0.001).
• PT showed a modest prolongation (13.2 ± 1.1 to 13.8 ± 1.4 s, p = 0.03); aPTT remained unchanged (31.1 ± 3.8 vs 31.6 ± 4.0 s, p = 0.21).

By 72 hours, platelet count partially recovered (226 ± 49 ×10³/µL), fibrinogen remained elevated (3.5 ± 0.9 g/L, p = 0.002), and D-dimer stabilized (1.08 ± 0.40 mg/L, p = 0.001). These findings suggest that CO₂-based angiography elicits measurable but moderate activation of coagulation. The increase in D-dimer and fibrinogen points to fibrin turnover and acute-phase response consistent with vascular intervention (Table 1). This is particularly relevant in patients with PAD and CKD, who already exhibit hemostatic dysregulation. [15,16]

Table 1. Hemostatic Parameters at Baseline, 24 Hours, and 72 Hours After Carboxyangiography

Within 24 hours of CO₂-based angiography, fibrinogen and D-dimer rose significantly while platelet count declined modestly, reflecting a moderate but transient coagulation activation. PT showed slight prolongation, and aPTT remained stable, suggesting preserved intrinsic pathway activity. These trends partially normalized by 72 hours, indicating limited systemic hemostatic perturbation following carboxyangiography.

Inflammatory and Oxidative Stress Biomarkers

High-sensitivity C-reactive protein (hs-CRP) baseline was 4.8 ± 2.2 mg/L. At 24 hours, it increased to 6.5 ± 2.9 mg/L (p < 0.001), and at 72 hours to 6.0 ± 2.7 mg/L (p = 0.002). Interleukin-6 (IL-6) rose from 7.4 ± 3.1 to 10.8 ± 4.5 pg/mL at 24 h (p < 0.001) and 9.9 ± 4.2 pg/mL at 72 h (p = 0.003). Malondialdehyde (MDA) as a marker of oxidative stress increased from 2.4 ± 0.6 to 3.0 ± 0.7 µmol/L at 24 h (p < 0.001) and remained elevated at 2.9 ± 0.6 µmol/L at 72 h (p = 0.002) (Figure 3). These data demonstrate that even with the kidney-sparing contrast modality, systemic inflammatory and oxidative responses occur post-angiography.

Figure 3. Inflammatory and Oxidative Stress Biomarker Changes after Carboxyangiography

A multivariate regression model adjusting for baseline eGFR, diabetes status, contrast volume (CO₂ + ICM), and CKD stage showed that greater contrast volume (per 10 mL increment) was independently associated with a larger reduction in eGFR (β = −0.9 mL/min/1.73 m², p = 0.01). Additionally, baseline fibrinogen >3.5 g/L was associated with more pronounced post-procedure D-dimer increases (OR 2.1; 95% CI 1.3–3.5; p = 0.002). Patients who developed CA-AKI had significantly higher baseline CRP (6.2 ± 2.4 vs 4.6 ± 2.0 mg/L, p = 0.01) and greater D-dimer rise (ΔD-dimer 0.56 ± 0.15 vs 0.34 ± 0.12 mg/L, p < 0.001) (Figure 4). No significant association was found between bailout ICM usage and CA-AKI incidence (p = 0.18), consistent with prior observations in CO₂ cohorts. [13].

Figure 4. Differences in baseline CRP and D-dimer response by CA-AKI status.

No procedure-related vascular complications (arterial dissection, embolism) or symptomatic gas-embolic events were recorded. Seven patients required extended hospitalization (> 5 days) due to comorbidities; two progressed to dialysis within 30 days (both had baseline eGFR <30 mL/min/1.73 m² and developed CA-AKI). Overall, in-hospital mortality was zero.

Summary of Findings

In this high-risk cohort, CO₂-based angiography demonstrated acceptable renal safety, with CA-AKI incidence of 6.9% lower than historical rates reported with iodinated contrast in similar CKD + CLI populations (~10–15%) [12,14]. Hemostatic activation occurred post-procedure (elevated fibrinogen and D-dimer, modest platelet drop), and inflammatory/oxidative stress biomarkers increased significantly. Importantly, baseline inflammatory/hemostatic status and contrast volume emerged as significant predictors of renal/hemostatic biomarker shifts. These findings support the renal-sparing advantage of CO₂ angiography in CKD patients undergoing lower limb interventions while highlighting that even with such approaches, systemic hemostatic and inflammatory perturbations remain.

Discussion

In this prospective study involving 130 retired military patients with concomitant critical limb ischemia (CLI) and chronic kidney disease (CKD), we investigated the impact of CO₂-based angiography (carboxyangiography) on renal function, hemostatic parameters, and systemic inflammatory and oxidative biomarkers. The major findings of our study were: (1) a modest but statistically significant post-procedural increase in serum creatinine and a corresponding decline in eGFR at 24 and 72 hours; (2) measurable activation of the coagulation cascade with elevated fibrinogen and D-dimer levels, along with a slight platelet reduction and PT prolongation; (3) increased systemic inflammatory and oxidative stress markers (hs-CRP, IL-6, MDA) at 24 hours that remained above baseline at 72 hours; and (4) the contrast volume and baseline fibrinogen were independent predictors of renal and hemostatic changes.

Renal Safety and Hemodynamic Considerations

Our study demonstrated that the incidence of contrast-associated acute kidney injury (CA-AKI) following CO₂ angiography was 6.9%, consistent with previously published data reporting rates between 7–14% in similar populations [6,7]. Wittig et al. observed a 13.2% incidence of AKI in patients with advanced CKD undergoing CO₂-guided interventions despite minimal iodinated contrast use [8]. Likewise, meta-analyses have confirmed that CO₂ angiography significantly reduces CA-AKI risk compared with conventional iodinated contrast angiography among patients with PAD and CKD [11]. Thus, our findings corroborate the renal-sparing potential of CO₂ angiography in high-risk vascular populations.

Nevertheless, the modest decline in eGFR and slight creatinine elevation in our cohort suggest that CO₂ angiography does not completely eliminate renal risk. These residual changes may reflect multifactorial injury mechanisms—such as microembolization, endothelial dysfunction, ischemic tubular damage, or pre-existing hemodynamic instability—rather than direct nephrotoxicity [1]. The independent association between total contrast volume and post-procedure eGFR reduction (β = −0.9 mL/min/1.73 m² per 10 mL increase, p = 0.01) emphasizes that even small additive doses of contrast, including minimal iodinated bailout use, can adversely affect renal function.

Hemostatic Activation and Coagulation Disturbance

We observed moderate but significant activation of hemostatic processes following CO₂-based angiography. Fibrinogen and D-dimer levels increased markedly and remained elevated at 72 hours, while platelet count showed a mild transient decline. PT was slightly prolonged, whereas aPTT remained unchanged. These findings align with prior studies suggesting that vascular manipulation and endothelial injury during angiography promote tissue factor release and systemic coagulation activation, even in the absence of large volumes of iodinated contrast [3].

Importantly, baseline fibrinogen concentration > 3.5 g/L was associated with a more pronounced rise in D-dimer (OR 2.1; 95% CI 1.3–3.5; p = 0.002), indicating that patients with an existing prothrombotic profile are more susceptible to post-procedural coagulation activation [5]. Previous evidence shows that elevated fibrinogen and D-dimer levels in patients with PAD and CKD predict worse outcomes, including higher rates of amputation and cardiovascular mortality [2]. Therefore, monitoring these parameters may be clinically useful for identifying patients at increased thrombotic risk following endovascular interventions.

Inflammatory and Oxidative Stress Responses

In parallel with hemostatic activation, inflammatory and oxidative stress markers increased significantly after angiography. hs-CRP rose from 4.8 ± 2.2 mg/L to 6.5 ± 2.9 mg/L (p < 0.001) at 24 hours, IL-6 increased from 7.4 ± 3.1 pg/mL to 10.8 ± 4.5 pg/mL (p < 0.001), and MDA levels, reflecting lipid peroxidation, rose from 2.4 ± 0.6 µmol/L to 3.0 ± 0.7 µmol/L (p < 0.001). Although these parameters declined slightly at 72 hours, they remained significantly elevated compared to baseline. This suggests a transient but systemic inflammatory and oxidative response induced by vascular instrumentation and reperfusion [12].

Several studies have shown that increased oxidative stress and inflammatory activation contribute to endothelial dysfunction and renal tubular injury, serving as key mediators of contrast-induced nephropathy and related vascular complications [13]. In this context, even though CO₂ lacks direct chemical nephrotoxicity, procedure-related inflammation and oxidative stress may account for residual renal impairment. The interplay between coagulation, inflammation, and oxidative stress likely represents a unified pathogenic mechanism driving microvascular and renal dysfunction in patients with CKD and CLI.

Clinical Implications

Our findings support the clinical utility of CO₂ angiography as a safer contrast alternative for patients with CKD and CLI. However, clinicians should recognize that renal and systemic perturbations can still occur, particularly among patients with pre-existing proinflammatory or prothrombotic states. A multimodal prevention strategy—limiting total contrast volume, optimizing hydration, avoiding nephrotoxic agents, and possibly attenuating inflammation and oxidative stress through pharmacologic means (e.g., statins, antioxidants)—may further mitigate risk [14].

Limitations

This study has several limitations. The cohort consisted exclusively of retired military patients, mostly male, which may limit external validity. The absence of a randomized iodinated-contrast control group precludes direct causal comparison. Follow-up was limited to 72 hours; thus, we did not assess long-term renal recovery or cardiovascular outcomes. Moreover, we did not include tubular injury biomarkers (e.g., NGAL, KIM-1) or assess microcirculatory renal perfusion changes, which might have provided additional mechanistic insight.

Conclusion

In conclusion, CO₂-based angiography demonstrated favorable renal safety compared with traditional iodinated contrast in high-risk patients with CLI and CKD, yet was associated with measurable transient declines in renal function and activation of hemostatic, inflammatory, and oxidative pathways. Baseline prothrombotic and inflammatory status and total contrast volume independently predicted the magnitude of these changes. These findings underscore that while CO₂ angiography reduces risk, it does not eliminate it, and careful patient selection, procedural optimization, and post-procedural monitoring remain crucial.

Acknowledgements

The authors express their sincere gratitude to the staff of the Military Medical Academy of the Armed Forces for their invaluable technical assistance and patient care during the study.