Association of Active Renin Content With Mortality in Critically Ill Patients: A Post hoc Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) Trial*

Abstract

Objective: Sepsis is a leading cause of mortality. Predicting outcomes is challenging and few biomarkers perform well. Defects in the renin–angiotensin system (RAS) can predict clinical outcomes in sepsis and may outperform traditional biomarkers. We postulated that RAS dysfunction (elevated active renin, angiotensin 1-7 [Ang-(1-7)], and angiotensin-converting enzyme 2 (ACE2) activity with depressed Ang-II and ACE activity) would be associated with mortality in a cohort of septic patients. Design: Post hoc analysis of patients enrolled in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized controlled trial. Setting: Forty-three hospitals across the United States. Patients: Biorepository samples of 103 patients. Interventions: We analyzed day 0 (within 24 hr of respiratory failure, septic shock, or both) and day 3 samples (n = 103 and 95, respectively) for assessment of the RAS. The association of RAS values with 30-day mortality was determined using Cox proportional hazards regression with multivariable adjustments for age, sex, VICTAS treatment arm, systolic blood pressure, Sequential Organ Failure Assessment Score, and vasopressor use. Measurements and Main Results: High baseline active renin values were associated with higher 30-day mortality when dichotomized to the median of 188.7 pg/mL (hazard ratio [HR] = 2.84 [95% CI, 1.10–7.33], p = 0.031) or stratified into quartiles (Q1 = ref, HRQ2 = 2.01 [0.37–11.04], HRQ3 = 3.22 [0.64–16.28], HRQ4 = 5.58 [1.18–26.32], p for linear trend = 0.023). A 1-sd (593.6 pg/mL) increase in renin from day 0 to day 3 was associated with increased mortality (HR = 3.75 [95% CI, 1.94–7.22], p < 0.001), and patients whose renin decreased had improved survival compared with those whose renin increased (HR 0.22 [95% CI, 0.08–0.60], p = 0.003). Ang-(1-7), ACE2 activity, Ang-II and ACE activity did not show this association. Mortality was attenuated in patients with renin over the median on day 0 who received the VICTAS intervention, but not on day 3 (p interaction 0.020 and 0.137, respectively). There were no additional consistent patterns of mortality on the RAS from the VICTAS intervention. Conclusions: Baseline serum active renin levels were strongly associated with mortality in critically ill patients with sepsis. Furthermore, a greater relative activation in circulating renin from day 0 to day 3 was associated with a higher risk of death.

Renin in critically ill patients

“…Furthermore, to analyze the effect of Ang II on mortality in relation to baseline renin levels, patients were divided into high and low renin groups using the median value as the threshold (172.7 pg/mL). The previously mentioned VICTAS post hoc analysis also showed a very similar median value of 188.7 pg/ml that dichotomized to high renin that was associated with mortality versus not [ 27 ]. Of note, compared to placebo, Ang II administration was significantly associated with reduced 28-day mortality in patients with high baseline renin values (hazard ratio [HR], 0.56; 95% confidence interval [CI] 0.35–0.88; P = 0.01) but not in those with low baseline renin values (HR, 1.11; 95% CI 0.66–1.86; P = 0.70).…”

“…Another study of 53 hypotensive patients on vasopressors found that the initial renin value after ICU admission and renin changes could predict hospital mortality [ 25 ]. A recent study also assessed the relationship between renin and mortality using the data of a previous RCT on a cocktail therapy of vitamins and corticosteroids in sepsis (VICTAS trial) [ 27 ]. This study found not only initial serum renin values but a relative increase in renin from day 0 to day 3 were associated with 30-day mortality after adjusting relevant confounding factors.…”

“…Elevated renin levels, rather than high vasopressor doses, appear to indicate the population who could likely benefit from Ang II therapy. Since high renin levels suggest inadequate circulating Ang II [ 35 ], renal hypoperfusion, or an inadequate conversion of renin to Ang II [ 27 ], exogenous Ang II administration could restore the dysfunctional RAS balance and reduce mortality in high-renin patients. Notably, in ATHOS-3, all the randomized patients received at least 0.2 µg/kg/min of norepinephrine equivalent vasopressors, but the lowest quartile renin value was 58 pg/mL in these patients [ 35 ].…”

“…In other words, only 25% of the study participants exhibited renin below that threshold [ 35 ]. Similarly, in VICTAS, the lowest quartile was 27 pg/mL [ 27 ]. Furthermore, in another cohort study on Ang II in vasodilatory shock, 4 out of 40 patients had renin levels < 40 pg/mL [ 33 ].…”

Impaired angiotensin II signaling in septic shock

“…Current evidence suggests that this crucial homeostatic system may falter in the context of septic shock. In critically ill patients, elevated renin concentration has been associated with lower blood pressure, a higher incidence of major adverse kidney events, and increased mortality rate and [35][36][37][38]. During catecholamine-resistant vasodilatory shock, mostly of septic origin, high renin concentration correlates with high circulating angiotensin I concentrations [36].…”