By Betty Tran, MD, MSc

Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago

Dr. Tran reports no financial relationships relevant to this field of study.

SYNOPSIS: Serum renin concentration in patients with catecholamine-resistant vasodilatory shock may identify those for whom treatment with angiotensin II has improved intensive care unit outcomes.

SOURCE: Bellomo R, Forni LG, Busse LW, et al. Renin and survival in patients given angiotensin II for catecholamine-resistant vasodilatory shock. Am J Respir Crit Care Med 2020;202:1253-1261.

The renin-angiotensin-aldosterone (RAAS) system plays an important role in regulating blood pressure. Renin, an enzyme secreted by the kidneys in response to sympathetic nerve activation, hypotension, or decreased sodium delivery to the distal tubule, cleaves angiotensinogen to angiotensin I. Angiotensin I then is cleaved by angiotensin-converting enzyme (ACE), an endothelial membrane-bound enzyme, to angiotensin II. Angiotensin II functions through a myriad of effects, including acting on the adrenal cortex to release aldosterone to increase sodium and fluid retention to elevate systemic vascular resistance and arterial pressure.

Physiologically, the premise for this study is based on the idea that endothelial injury seen in catecholamine-resistant vasodilatory shock (CRVS) leads to a decrease in ACE function, thereby increasing angiotensin I/II ratios and promoting high renin levels. Patients with high renin levels, therefore, may be a population most likely to benefit from treatment with angiotensin II.

This was a post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3)1 study, which enrolled adults with vasodilatory shock despite volume resuscitation with > 25 mL/kg and high-dose vasopressors (norepinephrine equivalent dose > 0.2 µg/kg/min). Participants were randomized 1:1 to receive saline placebo or angiotensin II, with the study drug started at 20 ng/kg/min adjusted during the first three hours to increase mean arterial pressure (MAP) to > 75 mmHg. Bellomo and colleagues obtained serum renal levels for 255 (79.4%) patients who participated in the original study. The median serum renin concentration was 172.7 pg/mL: (interquartile range [IQR] 60.7 pg/mL to 440.6 pg/mL), which was three-fold higher than the upper limit of normal. Renin levels positively correlated to angiotensin I/II ratios and angiotensin I levels. After three hours, patients treated with angiotensin II had significant reductions in renin and angiotensin I levels compared to placebo.

Patients were dichotomized by median serum renin concentration (i.e., above median renin and below median renin), with good balance between the placebo and angiotensin II treatment groups within these subpopulations. In a multivariable analysis, in patients with a renin concentration above the median, treatment with angiotensin II was associated with a decreased risk of mortality at 28 days (hazard ratio [HR] 0.62; 95% confidence interval [CI], 0.39–0.98, P = 0.0423). In contrast, there was no significant difference in mortality for those with serum renin concentrations below the median. Similarly, for the subset of patients with renin concentrations above the median, the rate of renal replacement therapy (RRT) liberation by day 7 was significantly higher in patients treated with angiotensin II compared to placebo (43% vs. 12%, P = 0.01), as was the rate of intensive care unit (ICU) discharge by day 28 (44% vs. 22%, respectively, P = 0.02). There were no differences in these outcomes between treatment groups in patients with renin concentrations below the median. The rate of ventilator liberation at day 7 did not differ significantly between treatment groups in either of the subpopulations.

COMMENTARY

When the results of ATHOS-3 first were published,1 it was encouraging to see positive results from a new class of vasopressor. However, several questions remained regarding its use: Is angiotensin II better than other agents already in use (e.g., norepinephrine, vasopressin, etc.)? Aside from raising MAP, are there more compelling outcomes associated with its use? Which patients are the best candidates to derive benefit from it?

Bellomo and colleagues attempted to address this last question. This study’s biggest strength and, arguably, impact is its consistency with known mechanisms and physiology related to the renin-angiotensin-aldosterone system. The investigators were able to show that renin levels positively correlated with baseline angiotensin I and angiotensin I/II ratios, the latter of which can be used as a surrogate for ACE activity. Consistent with prior findings,2 elevated renin levels were independently associated with an increased risk of death. In patients with elevated renin levels above the study median (172.7 pg/mL), treatment with synthetic angiotensin II was associated not only with lower renin levels after three hours, but also decreased 28-day mortality, liberation or freedom from RRT at day 7, and ICU discharge by day 28.

It is interesting to note that the MAP response in patients treated with angiotensin II vs. placebo was not affected by baseline renin level. In other words, even patients with renin concentrations below the study median had a MAP response to angiotensin II, despite not having improved outcomes. As such, the authors suggested that elevated renin levels may have other deleterious effects that may modify the effect by treatment group independent of MAP. For example, renin may activate receptors on leukocytes, resulting in the production of pro-inflammatory cytokines; the use of angiotensin II, by reducing renin levels, may modulate the inflammatory response and thereby improve survival. In addition, normalization of renin levels with angiotensin II may activate angiotensin II receptors in end organs, such as the kidneys, thereby increasing glomerular filtration rate and urine output and enhancing renal recovery.

This study has several notable limitations when evaluating their findings. First, the post hoc analysis requires validation in a prospective trial. Second, the finding that the effect of modification of renin on the treatment group was only present when renin was treated as a dichotomous variable (i.e., above or below the study median) as opposed to a continuous variable is arbitrary and should not be viewed as a physiologically meaningful cutoff. Third, the original ATHOS-3 trial was not stratified at baseline by renin level; therefore, differences in outcomes between the angiotensin II and placebo treatment groups in the subgroup of patients with higher renin level may be the result of chance imbalances in baseline characteristics.

Nevertheless, this study represents a strong start to defining how treatment effects can be heterogeneous, which patients may benefit the most from angiotensin II, and ultimately, how we can make more personalized, evidence-based decisions for our patients.

REFERENCES

  1. Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017;377:419-430.
  2. Gleeson PJ, Crippa IA, Mongkolpun W, et al. Renin as a marker of tissue-perfusion and prognosis in critically ill patients. Crit Care Med 2019;47:152-158.