Stronger Association of Intact Angiotensinogen with Mortality Than Lactate or Renin in Critical Illness: Post-hoc Analysis from the VICTAS Trial

Sepsis and septic shock remain global healthcare problems associated with high mortality rates despite best therapy efforts. Circulating biomarkers may identify those patients at risk for poor outcomes, however, current biomarkers, most prominently lactate, are non-specific and have an inconsistent impact on prognosis and/or disease management. Activation of the renin-angiotensin- system (RAS) is an early event in sepsis patients and elevated levels of circulating renin are more predictive of worse outcomes than lactate. The precursor protein Angiotensinogen is another key component of the circulating RAS; it is the only known substrate for renin and the ultimate source of the vasopressor Angiotensin II (Ang II). We postulate that lower Angiotensinogen concentrations may reflect a dysfunctional RAS characterized by high renin concentrations but attenuated Ang II generation, which is disproportionate to the high renin response and may compromise adequate support of blood pressure and tissue perfusion in septic patients. The current study compared the association between serum Angiotensinogen with mortality to that of lactate and renin in the VICTAS cohort of sepsis patients at baseline (day 0) by receiver operating characteristic (ROC) and Kaplan-Meier curve analyses. Serum concentration of Angiotensinogen was more strongly associated with 30-day mortality than either the serum concentrations of renin or lactate in sepsis patients. Moreover, the clinical assessment of Angiotensinogen may have distinct advantages over the typical measures of renin. The assessment of intact Angiotensinogen may potentially facilitate more precise therapeutic approaches (including exogenous angiotensin II) to restore a dysfunctional RAS and improve patient outcomes. Additional prospective validation studies are clearly required for this biomarker in the future.