Diagnostic Accuracy and Renal Safety of Carbon Dioxide Angiography in Lower Limb Angiography: A Systematic Review and Meta-Analysis

Background/Objectives: Iodinated contrast media (ICM) used in lower limb angiography carry risks of contrast-induced nephropathy (CIN) and allergic reactions, particularly in patients with peripheral arterial disease (PAD) and renal dysfunction. Carbon dioxide (CO2) angiography offers a potential non-nephrotoxic alternative. The purpose of this study was to evaluate the diagnostic accuracy and renal safety of CO2 angiography compared with ICM in patients undergoing lower limb angiography for PAD. Methods: A systematic search of PubMed, Scopus, and Web of Science was performed from inception to 4 September 2025. Studies comparing CO2 angiography with ICM in adult PAD patients were included. Risk of bias was assessed with QUADAS-2 for diagnostic accuracy studies and RoB 2 for randomised trials, and the methodological quality of comparative observational studies with the Newcastle–Ottawa Scale. Pooled sensitivity, specificity, adverse events, CIN, contrast volume, serum creatinine, and estimated glomerular filtration rate (eGFR) were analysed using random-effects models. Results: Nine studies (527 patients) were included. In three studies (111 patients) with extractable diagnostic accuracy data, CO2 angiography showed pooled sensitivity of 0.89 (95% confidence interval [CI]: 0.78–0.95) and specificity of 0.96 (95% CI: 0.85–0.99). Adverse events did not differ significantly between groups (four studies; risk ratio [RR] 0.63, 95% CI: 0.15–2.71), but discomfort during CO2 injection was common. CIN risk was lower with CO2 (two studies; RR 0.31, 95% CI: 0.14–0.73; p = 0.007), and contrast volume was reduced by a mean of 80.71 mL (two studies; p < 0.00001). Pooled serum creatinine and eGFR estimates showed extreme heterogeneity (I2 = 98–99%), with the two contributing studies reporting effects in opposite directions. Conclusions: In a small number of comparative studies, CO2 angiography showed pooled sensitivity and specificity compatible with clinically useful diagnostic performance, although these exploratory estimates derive from three studies with unblinded reference standards. The lower risk of CIN with CO2, observed in two studies, is hypothesis-generating, and CO2 has adverse effects of its own, principally discomfort during injection. These findings should be confirmed in larger prospective trials before CO2 can be regarded as an established alternative for patients at risk of CIN or iodine allergy.