Annals of Intensive Care

(2024) 14:79
Kotani et al. Annals of Intensive Care
https://doi.org/10.1186/s13613-024-01304-3

Open Access

REVIEW

Renin in critically ill patients
Yuki Kotani1 , Mark Chappell2, Giovanni Landoni3,4, Alexander Zarbock5, Rinaldo Bellomo6,7,8 andAshish K. Khanna9,10,11*   

Abstract
The renin-angiotensin system (RAS) constitutes one of the principal mechanisms to maintain hemodynamic and fluid
homeostasis. However, most research until now on RAS primarily focuses on its relationship with hypertension
and its role in critically ill hypotensive populations is not well understood. With the approval of angiotensin II (Ang II)
in the United States and Europe, following a phase 3 randomized controlled trial showing efficacy in catecholamineresistant vasodilatory shock, there is growing interest in RAS in critically ill patients. Among the fundamental components of RAS, renin acts as the initial stimulus for the entire system. In the context of hypotension, its release increases
in response to low blood pressure sensed by renal baroreceptors and attenuated negative Ang II feedback loop. Thus,
elevated renin could reflect disease severity and predict poor outcomes. Studies investigating this hypothesis havevalidated the prognostic accuracy of renin in various critically ill populations, with several reports indicating its superiority to lactate for mortality prediction. Accordingly, renin reduction has been used to assess the effectiveness of Ang
II administration. Furthermore, renin holds potential to identify patients who might benefit from Ang II treatment,
potentially paving the way for personalized vasopressor management. Despite these promising data, most available
evidence is derived from retrospective analysis and necessitates prospective confirmation. The absence of a rapid,
point-of-care and reliable renin assay presents another hurdle to its integration into routine clinical practice. This narrative review aims to describe the current understanding and future directions of renin as a biomarker during resuscitation of critically ill patients.
Keywords Renin, Angiotensin II, Biomarkers, Intensive care units, Mortality, Critical illness, Shock*Correspondence:
Ashish K. Khanna
akhanna@wakehealth.edu
1
Department of Intensive Care Medicine, Kameda Medical Center,
Kamogawa, Japan
2Hypertension and Vascular Research Center, Wake Forest University
School of Medicine, Winston‑Salem, NC, USA
3
Department of Anesthesia and Intensive Care, IRCCS San Raffaele
Scientific Institute, Milan, Italy
4
School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
5
Department of Anesthesiology, Intensive Care Medicine and Pain
Therapy, University Hospital Muenster, Muenster, Germany
6
Department of Intensive Care, Austin Hospital, Melbourne, Australia
7
Australian and New Zealand Intensive Care Research Centre, Monash
University, Melbourne, Australia
8
Department of Critical Care, Melbourne Medical School, The Universityof Melbourne, Melbourne, Australia
9
Section On Critical Care Medicine, Department of Anesthesiology, Wake
Forest University School of Medicine, Winston‑Salem, NC 27157, USA
10
Perioperative Outcomes and Informatics Collaborative, Wake Forest
University School of Medicine, Medical Center Boulevard, Winston‑Salem,
NC 27157, USA

11

Outcomes Research Consortium, Cleveland, OH 44195, USA© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
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Kotani et al. Annals of Intensive Care

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Background
Although hypotension is a major clinical issue in theintensive care unit (ICU), previous research had focused
primarily on catecholamines and vasopressin as vasoactive agents. Only recently, however, the results of a phase
3, multinational, randomized controlled trial (RCT) of
angiotensin II (Ang II) in catecholamine-resistant vasodilatory shock (ATHOS-3 trial) [1], followed by its approvalin the United States and Europe have attracted attention
toward RAS from the intensive care community and fostered clinical studies to elucidate its role among criticallyill patients. This review aims to summarize recent findings of elevated renin and its downstream derivatives incritically ill patients, with a special focus on its predictive
performance of clinically relevant outcomes and its role
as a marker of the efficacy of Ang II therapy, and future
perspectives on its use in ICU settings.
Main text
Pathophysiology of renin‑angiotensin system dysfunction

The RAS forms one of the main mechanisms that control blood pressure, fluid balance, and ionic composition (i.e., sodium, chloride, and potassium). Initially,
angiotensinogen, synthesized in the liver and released
into the circulation, undergoes cleavage by renin—aproteolytic enzyme secreted by renal juxtaglomerular cells—to generate angiotensin I (Ang I) [2]. Due tothe very high concentrations of vascular and circulating angiotensin-converting enzyme (ACE), the Ang I
decapeptide is immediately processed to Ang II, whichis the primary effector peptide of the classical RAS axis

Page 2 of 8[3]. Ang II exerts multiple physiologic actions, including vasoconstriction by binding to the Ang II type I
receptor ­(AT1R) [3, 4].
In contrast, there is the potential for an alternative
pathway that counterbalances the classical axis, primarily
through the effector molecule angiotensin-(1–7) (Ang(1–7)). The synthesis of Ang-(1–7) includes its transformation from Ang II by ACE2 [5] and direct generationfrom Ang I by the action of metalloendopeptidases suchas neprilysin [6, 7] (Fig. 1). By binding to its unique Mas
receptor, Ang-(1–7) can mitigate the physiological andpathological effects of the classic pathway, thereby exhibiting vasodilatory, natriuretic, anti-inflammatory, andanti-fibrotic effects [8]. Conditions that influence thebinding of Ang II to the A­ T1R versus ACE2-dependent
metabolism of the peptide involve the relative concentrations of the ­AT1R and ACE2 in a particular tissue undernormal or pathological situations [9]. The A­ T1R exhibits a greater preference for Ang II ­(KD of ~ 1 nM) than
ACE2 ­(KM of ~ 2 µM) [9]. However, pathological conditions such as septic shock may reduce ­AT1R expression
and increase ACE2 that would favor processing of Ang II
to Ang-(1–7). Reduced levels of ACE in septic shock may
also promote the direct conversion of Ang I to Ang-(1–7)
by neprilysin [9]. ACE2 also cleaves Ang I to Ang-(1–9)
that may stimulate the Ang II type II receptor, whichshares similar actions of Ang-(1–7) to antagonize theclassical Ang II-AT1R pathway [10]. In contrast to ACE2,
ACE metabolizes Ang-(1–7) to Ang-(1–5) and is the primary route for degradation of the peptide in the circulation [9].

Fig. 1 Classical and alternative pathways of the renin-angiotensin system. ACE angiotensin-converting enzyme, AT1R angiotensin II type I receptor,
AT2R angiotensin II type II receptor, AT4R angiotensin II type IV receptor, DPP3 dipeptidyl peptidase 3, NEP neprilysin

Kotani et al. Annals of Intensive Care

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Dipeptidyl peptidase 3 (DPP3), a cytosolic zincdependent amino dipeptidase ubiquitously expressed inhuman cells and tissues, plays a role in modulating peptides involved in both the classical and alternative RAS
pathways. Under normal conditions, intracellular levels of DPP3 act as a regulator of the oxidative stress andimmunological response [11]. However, in critical illness,the cellular release of DPP3 due to tissue injury increases
circulating levels of the peptidase that may contributeto the metabolism of vasoactive peptides [11]. Although
we find that human proximal tubule cells released DPP3
into the cell media and subsequently utilized these cells
to purify and characterize human DPP3, our studies did
not identify processes involved in the secretion of theaminopeptidase [12, 13]. Indeed, to our knowledge, thefactors that govern the expression and regulated releaseof the enzyme are currently unknown [11, 13]. DPP3
catalyzes the hydrolysis of Ang-(1–7) into Ang-(3–7),
which is immediately converted to Ang-(5–7), while
DPP3 cleaves Ang II to Ang IV (Ang-(3–8)), and thenAng-(5–8) (Fig. 1) [13]. Ang IV binds to Ang II type IV
receptor to exert vasodilation, cardioprotective effects,
and natriuresis [14]. DPP3 does not cleave larger peptides(≥ 10 amino acids) such as Ang I [9, 13, 15, 16].
Under physiological conditions, triggers such as
hypotension, sympathetic nervous system stimulation,and reduced Ang II generation (loss of negative feedback), may provoke renin secretion. Conversely, critically ill hypotensive patients often exhibit impaired RAS
signaling characterized by downregulation of ­AT1R
expression [17] and a reduced ACE activity [18]. These
alterations may further worsen hypotension and dysregulated immune effects via lack of endogenous Ang II or its
active site of action.
Outcome prediction

RAS dysregulation during critical illness has been documented for several decades [19]. A broad review ofobservational data has suggested that the predictive
performance of serum renin is reliably high across various critically ill and perioperative settings [20]. Since
decreased blood pressure and reduced organ perfusion are major triggers for renin secretion, hypotensive patients are the most studied population, and mostdata showed an association of serum renin with mortality [21–26]. Of these studies, three identified renin
as an independent mortality risk factor after multivariable adjustment [21, 22, 25]. For example, a monocentric prospective study of 20 heterogenous shock
patients reported a significantly greater change of serum
renin levels in non-survivors than survivors (92 ± 57 vs.
−32 ± 57 µU/mL) [23]. Another study of 53 hypotensive
patients on vasopressors found that the initial renin value

Page 3 of 8

after ICU admission and renin changes could predict
hospital mortality [25]. A recent study also assessed therelationship between renin and mortality using the dataof a previous RCT on a cocktail therapy of vitamins andcorticosteroids 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 associatedwith 30-day mortality after adjusting relevant confounding factors. Interestingly, patients had a survival advantage when their renin decreased over time compared tothose whose values of this biomarker increased. This firstof kind analysis also examined other components of the
RAS pathway and did not find an association of Ang II,
ACE 2 and Ang (1–7) with mortality. While lactate has
been suggested for use to guide resuscitation in the surviving sepsis guidelines [28] and is widely used in ICUs,
especially among high-income countries, using lactate asa resuscitation target requires cautious evaluation since
hyperlactemia may occur for reasons other than tissue
hypoperfusion or increased production (e.g., hypoperfusion and excessive β adrenergic stimulation via epinephrine use) or suppressed excretion due to liver failure [29].
Notably, two studies compared the predictive performance for mortality between renin and lactate [23, 25].
The area under the receiver operating characteristics(AUROC) was 0.80 for maximum renin level and 0.70
for maximum lactate level for the first study [23], whilethat for initial renin and lactate was 0.682 and 0.615,
respectively in the latter study [25]. Therefore, Jeyaraju
and colleagues demonstrated that both absolute renin
and lactate predict mortality whereas only an increase ofrenin and not lactate over 72 h had an independent association with mortality [25]. In addition, there was a higher
proportion of renin > 40 pg/mL than lactate > 2 mmol/Lin non-survivors than survivors [25].
From a physiological point of view, circulating reninquickly and directly reflects hemodynamic changes
because hypotension is the main trigger of its secretion,and the half-life of renin is short (approximately 10 min).
Taken together, these preliminary data may suggest thepotential utility of renin as a promising perfusion marker.
Apart from mortality, renin can also predict adverse
renal outcomes [24, 30–32]. In a small study of 41 septic
shock patients, plasma renin concentration was associated with receipt of renal replacement [24]. A prospective
cohort study of 197 cardiac surgery patients investigated
if changes in circulating renin levels between before and
4 h after surgery could predict postoperative AKI within
72 h [31]. When divided into two groups with the medianrenin increase (3.7 µU/mL) as reference, patients with agreater renin increase after surgery were more likely toexperience postoperative AKI. The predictive value of
postoperative renin was relatively high (AUROC of 0.80).

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The relationship between renin and major adverse kidney events (MAKE) at hospital discharge was assessed in
280 heterogenous ICU patients [30]. MAKE was defined
as a composite endpoint of mortality, renal replacement
therapy dependence, and reduction in estimated glomerular filtration rate to ≤ 75%. When 280 patients werecategorized into three groups according to serum reninlevels (median renin levels of 7.2 pg/mL in the first tertile, 40.7 pg/mL in the second tertile, and 355.3 pg/mL in
the third tertile), multivariable logistic regression analyses showed that compared to the lowest renin group, theintermediate and high renin groups were at a higher riskof MAKE at hospital discharge.
When assessing renin in vasodilatory shock, cautious consideration should be given to previous use of
RAS inhibitors (i.e., ACE inhibitors and Ang II receptor blockers [ARBs]). A single-center prospective cohort
study found that recent exposure to RAS inhibitors was
significantly associated with an increased renin levels, nearly doubling them [33]. A post-hoc analysis of aphase 3 RCT on Ang II in vasodilatory shock was also
conducted to evaluate the relationship between previous RAS inhibitors use and renin levels [34]. When compared to patients without recent RAS inhibitor exposure,
those who had received ACE inhibitors exhibited higher
renin levels at baseline [34]. Furthermore, exogenous Ang
II administration reduced renin levels at 3 h in patients
without RAS inhibitor exposure and those with ACE
inhibitor exposure but not in those with ARBs exposure[34]. These observations align with physiological negative feedback of RAS and pharmacological mechanismsof action of ACE inhibitors, ARBs, and Ang II.
Current evidence suggests that renin release fromjuxtaglomerular cells of the kidney is triggered by hypoperfusion of the renal medulla or decreased endogenous
Ang II or a combination of these factors. In addition, abaseline, a threshold difference and a change in renin
may outperform lactate in terms of mortality prediction.
However, no dedicated data is available as to whether
renin can reflect the balance between tissue oxygen
demand and supply.
Treatment response

Given that renin release is regulated by a negative feedback loop by Ang II generation, it is a reasonable hypothesis that increased serum renin concentrations could
serve as an indicator of reduced Ang II levels and ora dysfunctional and unstable RAS, thereby acting as apotential trigger for exogenous Ang II administration.
Furthermore, decreased serum renin levels after Ang II
infusion may imply a degree of efficacy of Ang II therapy
because of an association of renin with adverse clinicaloutcomes [20].

Page 4 of 8

Vasodilatory shock

The ATHOS-3 trial which randomly assigned catecholamine-resistant vasodilatory shock patients either to Ang
II or to placebo (which included continuation of background non-Ang II vasopressors). Patients who received
Ang II had a sharp and significant decline in serum reninin the first 3 h compared to the placebo group whererenin was unchanged. A secondary analysis was performed to investigate the relationship between Ang II
treatment and renin changes between randomizationand 3 h after the study drug initiation [35]. Serum reninlevels at randomization were similar in the two groups(146.1 pg/mL in the Ang II group and 193.7 pg/mL in
the placebo group, P = 0.42). At 3 h, greater renin reduction was observed in the Ang II group (median, 54.3%;
interquartile range [IQR], 37.9 to 66.5% reduction) thanin the placebo group (median, 14.1%; IQR, 37.6% reduction to 5.1% increase), which was statistically significantly
different (P < 0.0001). Furthermore, to analyze the effectof 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 withmortality 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 withlow baseline renin values (HR, 1.11; 95% CI 0.66–1.86;
P = 0.70). Multivariable analyses confirmed that increased
renin at randomization was an independent risk factor
for 28-day mortality and that Ang II administration was
associated with mortality risk reduction in patients withhigh baseline renin values.
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 thedysfunctional RAS balance and reduce mortality in highrenin 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 otherwords, 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 anothercohort study on Ang II in vasodilatory shock, 4 out of
40 patients had renin levels < 40 pg/mL [33]. Given that
normal renin level is typically considered < 40 pg/mL,

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the proportion of patients with low renin levels in septic
shock or vasodilatory shock appears to range from 10 to
25% and this group may not be responsive to exogenous
Ang II.
Regarding the relationship between baseline vasopressor requirements and Ang II therapy, another post-hoc
analysis of ATHOS-3 showed that a subgroup sufferingfrom more severe shock (i.e., norepinephrine equivalence > 0.25 µg/kg/min), did not benefit from Ang II
treatment; while the other subgroup (norepinephrine
equivalence was between 0.2 and 0.25 µg/kg/min) experienced reduced mortality when assigned to Ang II[36]. Thus, Ang II therapy may carry survival benefits inpatients who show high renin values or have not reachedhigh norepinephrine equivalence.
Despite the retrospective design, these observations
suggest valuable insights into RAS dynamics and thepotential utility of renin-guided Ang II therapy in catecholamine-resistant vasodilatory shock patients.
Cardiac surgery

Several studies have evaluated the effect of Ang II treatment on renin concentrations among cardiac surgery
populations. The first was a retrospective cohort study
in 40 cardiac surgery patients who had an increase inrenin at 4 h after cardiopulmonary bypass compared topreoperative levels (> 3.7 µU/mL) and received continuous norepinephrine infusion [32]. The cutoff for the reninincrease was defined by evidence from previous literaturethat this value defined a higher risk of worse outcomes[31]. Among these patients, 20 received Ang II in addition to norepinephrine in the postoperative course and
20 underwent usual care without Ang II. When adjusted
by the renin level at 4 h after surgery, renin levels at
12 h after surgery were significantly lower in the Ang IIgroup than in the usual care group (71.7 µU/mL [IQR,
21.9–211.4] vs.130.6 µU/mL [IQR, 62.9–317.0]; adjusted
P = 0.034). In addition, Ang II administration, comparedwith usual care, was associated with reduced cumulative norepinephrine dose (1.33 mg [IQR, 0.78–2.04] vs.
3.25 mg [IQR, 1.00–4.75]; P = 0.046).
The first randomized trial comparing the intraoperative
infusion of Ang II with that of norepinephrine in cardiac
surgery patients was performed as a feasibility trial [37].
Following the confirmatory results regarding adherence
without any concerns for adverse events [37], the authors
explored the effect of Ang II on RAS within this randomized trial [38]. Compared to baseline, the renin level at
ICU admission significantly increased in the norepinephrine group (52 [IQR, 115–137] vs. 112 [IQR, 49–410]µU/mL; P < 0.001), but not in the Ang II group (87 [IQR,
40–232] vs. 82 [IQR, 24–172] µU/mL; P = 0.36). At 24 hfollowing surgery, renin levels increased in both groups.

Page 5 of 8

An important limitation was that only 4/28 patients in
the Ang II group received the study drug longer than
24 h. An additional analysis was also performed to test
whether the preoperative RAS inhibitor use affected
the renin kinetics and it found significantly higher reninlevels before surgery in patients with preoperative RAS
inhibitor therapy than those without.
Considering the physiological background and preliminary data suggesting that renin could identify patients
who would benefit from Ang II therapy, a randomized
trial tested the hypothesis that Ang II reduces the kidney stress in vasoplegic cardiac surgery patients witha renin increase after surgery [39]. Among 63 patients,
31 were randomized to the Ang II group and 32 to theplacebo group. Although kidney stress, measured by thedifference in Nephrocheck® values (tissue inhibitor of
metalloproteinases-2 [TIMP-2])*(insulin-like growth factor-binding protein 7 [IGFBP7]), was not significantly different (median, 0.06 vs. -0.08 [ng/mL]2; P = 0.19), Ang II,
compared to placebo, reduced fluid administration (2946
vs. 3341 mL; P = 0.03) and norepinephrine dose (0.19 vs.
4.18 mg; P < 0.001) [39].
Table 1 summarizes the findings regarding renin in thecontext of randomized trials in intensive care settings.
Logistic and economic issues

The biggest challenge to incorporate renin into ICUbased treatment protocols is a limited availability of apoint-of-care renin assay that completely distinguishes
prorenin [40]. Given the urgency of shock management,
the results of renin tests should also be available at least
within one hour, ideally within 10 min as typically performed with lactate. This is not yet possible althoughpromising technology using enzyme-linked immunosorbent assays (ELISA) based techniques may be on thehorizon.
Another consideration is the method of measurementof renin levels. A scoping review of renin in critically ill
and perioperative settings identified heterogeneity in themeasurement methods (i.e., renin activity vs. renin concentration) [20]. Moreover, plasma renin activity values
are influenced by angiotensinogen, prorenin, and sample handling (i.e., cryoactivation of prorenin) and therequired steps to generate and quantify Ang I levels [9].
On the other hand, newly developed dual antibody-based
ELISAs, are a preferable method to directly determine
active circulating renin concentrations, which can differentiate renin and prorenin and does not require an Ang
I generation step from either endogenous (plasma renin
activity) or exogenous angiotensinogen (plasma reninconcentration) that greatly simplifies the assay [9].
Conducting a cost–benefit analysis is crucial, particularly in the context of incorporating novel technologies

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Table 1 Data on renin in randomized trials of critically ill settings
First author, year

Population

Patients Intervention

Comparator

Results
Compared to placebo, Ang II therapy was associated with greater reduction in renin levels
In the high renin group (> 172.7 pg/mL), Ang II
therapy was associated with reduced mortality

Bellomo R 2020 [35] Refractory vasodilatory shock 255

Angiotensin II

Placebo

Coulson T 2023 [38] Cardiac surgery

60

Angiotensin II

Norepinephrine Renin release was suppressed in the Ang II groupcompared to the norepinephrine group

Busse LW 2023 [27]103

Vitamin C, thiamine, hydrocortisone

PlaceboBaseline renin values and a relative renin changeover three days were associated with mortality

60

Angiotensin II

PlaceboRenin increase between preoperative and postoperative values (> 3.7 µU/mL) was used
as an inclusion criterion
No significant difference was observed in kidney
stress detected by renal biomarkers

Sepsis and septic shock

Sadjadi M 2024 [39] Cardiac surgery

into standard clinical practice. The measurement ofserum or plasma renin levels, which can be conductedin most laboratories at a relatively low cost (around 10
euros per assay), offers a notable example. Given the documented potential of renin to predict adverse outcomes[23, 25, 31] and identify patients who could respondfavorably to Ang II treatment [35], the routine assessment of serum renin levels may enhance patient carequality. However, no economic evaluation has yet been
conducted regarding the use of renin measurement in
intensive care settings.
Future perspective

Based on the current evidence, potential clinical application of renin in critically ill patients include prognostication, guide for Ang II initiation, and real time dynamic
resuscitation targets. Moreover, renin can be used inclinical research as an inclusion criterion and surrogate
endpoint (Table 2).
To further clarify the role of renin in critically illpatients, there are several research topics to be addressed.
First, there are still uncertainties regarding renin kinetics. Given the rapid changes in hemodynamic conditions
and therapeutic interventions during the initial phaseof shock, serial renin measurements within that period

may help guide management. However, previous studies
have measured renin levels once or twice during the initial 24 h [20]. A study with two measurements within the
24-h window reported renin at randomization and 3 hafter the study drug initiation, which highlights the needfor more frequent measurements to elucidate how reninchanges over time [35]. Moreover, whether absolute or
relative renin values are better is also a matter of investigation. In cardiac surgery patients, relative changes inrenin before and after surgery were better than the postoperative absolute value in terms of AKI prediction [31].
However, no study has specifically compared the predictive validity between absolute values and relative changes
within a short duration in other populations.
Second, renin may help guide hemodynamic management. Since renin may outperform lactate in predicting mortality [23, 25], using renin instead of lactate asa resuscitation target could improve clinical outcomes.
Future research should address the optimal reliable renin
cutoff value for successful resuscitation. In addition, bedside renin assay availability is essential to allow for serial
measurements and timely treatment adjustment according to renin levels.
Third, high renin levels could identify patients who may
benefit from Ang II administration given the data from

Table 2 Potential application of renin in critically ill settings
Role

Explanation

Prognostic factor

Renin is associated with mortality, adverse renal outcomes, and hemodynamic instability
Renin may predict mortality better than lactate

Guide to start angiotensin II

High renin levels may indicate the effectiveness of angiotensin II administration

Resuscitation target

Compared to lactate, renin may predict mortality better and be less influenced by reasons otherthan hypoperfusion

Inclusion criteria

Using renin as an inclusion criterion will identify patients at risk of developing such complications

Outcome measures

The association of renin with mortality suggests its utility as a surrogate outcome

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ATHOS-3 trial [35]. Although a randomized trial did
not show renoprotective effects of Ang II as the first-line
vasopressor in hyperreninemic cardiac surgery patients,
any definitive conclusion cannot be made due to its small
sample size [39]. Finally, we need to evaluate and establish the most complete assessment of renin in the plasmaof septic shock patients that associates with disease
severity and outcome by using a combination of assays(prorenin, renin, ACE, aldosterone and their ratios) to
plasma renin activity.

Conclusions
Recent studies have shed a light on the role of RAS in the
management of critically ill patients. Renin is consistently
associated with poor outcomes across different patientcategories and its predictive accuracy may outperformthat of lactate. Renin may help identify patients who arelikely to benefit from Ang II infusion, which provides a
promising hypothesis for future randomized trials. The
development of point-of-care renin assay is crucial for its
application in clinical settings.
Abbreviations
ACE	Angiotensin-converting enzyme
AKI	Acute kidney injury
Ang I	Angiotensin I
Ang II	Angiotensin II
AT1R	Angiotensin II type I receptor
AUROC	Area under the receiver operating characteristics
DPP3	Dipeptidyl peptidase 3
ELISA	Enzyme-linked immunosorbent assayHR	Hazard ratio
ICU	Intensive care unit
IGFBP7	Insulin-like growth factor-binding protein 7
IQR	Interquartile range
MAKE	Major adverse kidney events
RAS	Renin-angiotensin system
RCT​	Randomized controlled trial
TIMP-2	Tissue inhibitor of metalloproteinases-2
Acknowledgements
Not applicable.
Author contributions
Conceptualization, literature searching strategy and data extraction: YK, MC,
LG, AZ, RB, AKK. Writing—original draft: YK. Writing—review, editing andenhancement: MC, LG, AZ, RB, AKK. Preparation of figure: YK, MC. All authors
read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The data presented in this manuscript are available from the corresponding
author upon reasonable request.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.

Page 7 of 8Competing interests
The authors report no competing interests.
Received: 14 March 2024 Accepted: 28 April 2024

References
1. Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al.
Angiotensin II for the treatment of vasodilatory shock. N Engl J Med.
2017;377:419–30.
2. Peti-Peterdi J, Harris RC. Macula densa sensing and signaling mechanismsof renin release. J Am Soc Nephrol. 2010;21:1093–6.
3. Li Q, Feenstra M, Pfaffendorf M, Eijsman L, van Zwieten PA. Comparative
vasoconstrictor effects of angiotensin II, III, and IV in human isolated
saphenous vein. J Cardiovasc Pharmacol. 1997;29:451.
4. Wolf G, Wenzel U, Burns KD, Harris RC, Stahl RAK, Thaiss F. Angiotensin II
activates nuclear transcription factor-kappaB through AT1 and AT2 receptors. Kidney Int. 2002;61:1986–95.
5. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N,
et al. A novel angiotensin-converting enzyme-related carboxypeptidase(ACE2) converts angiotensin I to angiotensin 1–9. Circ Res. 2000;87:E1-9.
6. Yamamoto K, Chappell MC, Brosnihan KB, Ferrario CM. In vivo metabolismof angiotensin I by neutral endopeptidase (EC 3.4.24.11) in spontaneously
hypertensive rats. Hypertension. 1992;19:692–6.
7. Chappell MC, Marshall AC, Alzayadneh EM, Shaltout HA, Diz DI. Updateon the Angiotensin converting enzyme 2-Angiotensin (1–7)-MAS receptor axis: fetal programing, sex differences, and intracellular pathways.
Front Endocrinol. 2014;4:201.
8. Santos RA. Angiotensin-(1–7). Hypertension. 2014;63:1138–47.
9. Chappell MC. Biochemical evaluation of the renin-angiotensin
system: the good, bad, and absolute? Am J Physiol Heart Circ Physiol.
2016;310:H137–52.
10. Steckelings UM, Widdop RE, Sturrock ED, Lubbe L, Hussain T, Kaschina E,
et al. The angiotensin AT2 receptor: from a binding site to a novel therapeutic target. Pharmacol Rev. 2022;74:1051–135.
11. Malovan G, Hierzberger B, Suraci S, Schaefer M, Santos K, Jha S, et al.
The emerging role of dipeptidyl peptidase 3 in pathophysiology. FEBS J.
2023;290:2246–62.
12. Wilson BA, Cruz-Diaz N, Marshall AC, Pirro NT, Su Y, Gwathmey TM, et al.
An angiotensin-(1–7) peptidase in the kidney cortex, proximal tubules,
and human HK-2 epithelial cells that is distinct from insulin-degrading
enzyme. Am J Physiol Renal Physiol. 2015;308:F594-601.
13. Cruz-Diaz N, Wilson BA, Pirro NT, Brosnihan KB, Marshall AC, Chappell
MC. Identification of dipeptidyl peptidase 3 as the angiotensin-(1–7)
degrading peptidase in human HK-2 renal epithelial cells. Peptides.
2016;83:29–37.
14. Paz Ocaranza M, Riquelme JA, García L, Jalil JE, Chiong M, Santos RAS,
et al. Counter-regulatory renin-angiotensin system in cardiovasculardisease. Nat Rev Cardiol. 2020;17:116–29.
15. Deniau B, Picod A, Van Lier D, Vaittinada Ayar P, Santos K, Hartmann O,
et al. High plasma dipeptidyl peptidase 3 levels are associated with mortality and organ failure in shock: results from the international, prospective and observational FROG-ICU cohort. Br J Anaesth. 2022;128:e54–7.
16. Jha S, Taschler U, Domenig O, Poglitsch M, Bourgeois B, Pollheimer M,
et al. Dipeptidyl peptidase 3 modulates the renin-angiotensin system inmice. J Biol Chem. 2020;295:13711–23.
17. Leisman DE, Fernandes TD, Bijol V, Abraham MN, Lehman JR, Taylor MD,
et al. Impaired angiotensin II type 1 receptor signaling contributes tosepsis-induced acute kidney injury. Kidney Int. 2021;99:148–60.
18. Zhang W, Chen X, Huang L, Lu N, Zhou L, Wu G, et al. Severe sepsis: low
expression of the renin-angiotensin system is associated with poor prognosis. Exp Ther Med. 2014;7:1342–8.
19. Zipser RD, Davenport MW, Martin KL, Tuck ML, Warner NE, Swinney RR,
et al. Hyperreninemic hypoaldosteronism in the critically ill: a new entity.
J Clin Endocrinol Metab. 1981;53:867–73.
20. Kotani Y, Belletti A, Maiucci G, Lodovici M, Fresilli S, Landoni G, et al. Renin
as a prognostic marker in intensive care and perioperative settings: a

Kotani et al. Annals of Intensive Care

21.
22.

23.
24.
25.

26.

27.

28.

29.
30.
31.

32.
33.

34.

35.

36.

37.
38.

39.

(2024) 14:79

scoping review. Anesth Analg. 2023. https://​doi.​org/​10.​1213/​ANE.​00000​
00000​006682.
Tamion F, Le Cam-Duchez V, Menard JF, Girault C, Coquerel A, Bonmarchand G. Erythropoietin and renin as biological markers in critically illpatients. Crit Care. 2004;8:R328–35.
Chung KS, Song JH, Jung WJ, Kim YS, Kim SK, Chang J, et al. Implications of plasma renin activity and plasma aldosterone concentration in critically ill patients with septic shock. Korean J Crit Care Med.
2017;32:142–53.
Gleeson PJ, Crippa IA, Mongkolpun W, Cavicchi FZ, Van Meerhaeghe T,
Brimioulle S, et al. Renin as a marker of tissue-perfusion and prognosis in
critically ill patients. Crit Care Med. 2019;47:152–8.
Nguyen M, Denimal D, Dargent A, Guinot PG, Duvillard L, Quenot JP, et al.
Plasma renin concentration is associated with hemodynamic deficiency
and adverse renal outcome in septic shock. Shock. 2019;52:e22-30.
Jeyaraju M, McCurdy MT, Levine AR, Devarajan P, Mazzeffi MA, Mullins
KE, et al. Renin kinetics are superior to lactate kinetics for predicting
in-hospital mortality in hypotensive critically ill patients. Crit Care Med.
2022;50:50–60.
Leśnik P, Łysenko L, Krzystek-Korpacka M, Woźnica-Niesobska E,
Mierzchała-Pasierb M, Janc J. Renin as a marker of tissue perfusion, septic
shock and mortality in septic patients: a prospective observational study.
Int J Mol Sci. 2022. https://​doi.​org/​10.​3390/​ijms2​31691​33.
Busse LW, Schaich CL, Chappell MC, McCurdy MT, Staples EM, Ten Lohuis
CC, et al. Association of active renin content with mortality in critically illpatients: a post hoc analysis of the vitamin C, thiamine, and steroids insepsis trial. Crit Care Med. 2023. https://​doi.​org/​10.​1097/​CCM.​00000​00000​
006095.
Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, FrenchC, et al. Surviving sepsis campaign: international guidelines for
management of sepsis and septic shock 2021. Intensive Care Med.
2021;47:1181–247.
Hernandez G, Bellomo R, Bakker J. The ten pitfalls of lactate clearance insepsis. Intensive Care Med. 2019;45:82–5.
Flannery AH, Ortiz-Soriano V, Li X, Gianella FG, Toto RD, Moe OW, et al.
Serum renin and major adverse kidney events in critically ill patients: amulticenter prospective study. Crit Care. 2021;25:294.
Küllmar M, Saadat-Gilani K, Weiss R, Massoth C, Lagan A, Cortés MN,
et al. Kinetic changes of plasma renin concentrations predict acutekidney injury in cardiac surgery patients. Am J Respir Crit Care Med.
2021;203:1119–26.
Meersch M, Weiss R, Massoth C, Küllmar M, Saadat-Gilani K, Busen M, et al.
The association between angiotensin II and renin kinetics in patients after
cardiac surgery. Anesth Analg. 2022;134:1002–9.
See EJ, Chaba A, Spano S, Maeda A, Clapham C, Burrell LM, et al. Renin
levels and angiotensin II responsiveness in vasopressor-dependent hypotension. Crit Care Med. 2024. https://​doi.​org/​10.​1097/​CCM.​00000​00000​
006273.
Leisman DE, Handisides DR, Busse LW, Chappell MC, Chawla LS, Filbin MR,
et al. ACE inhibitors and angiotensin receptor blockers differentially alter
the response to angiotensin II treatment in vasodilatory shock. Crit Care.
2024;28:130.
Bellomo R, Forni LG, Busse LW, McCurdy MT, Ham KR, Boldt DW, et al.
Renin and survival in patients given angiotensin ii for catecholamineresistant vasodilatory shock. A clinical trial. Am J Respir Crit Care Med.
2020;202:1253–61.
Wieruszewski PM, Bellomo R, Busse LW, Ham KR, Zarbock A, Khanna AK,
et al. Initiating angiotensin II at lower vasopressor doses in vasodilatory
shock: an exploratory post-hoc analysis of the ATHOS-3 clinical trial. Crit
Care. 2023;27:175.
Coulson TG, Miles LF, Serpa Neto A, Pilcher D, Weinberg L, Landoni G, et al.
A double-blind randomised feasibility trial of angiotensin-2 in cardiac
surgery*. Anaesthesia. 2022;77:999–1009.
Coulson TG, Miles LF, Zarbock A, Burrell LM, Patel SK, von Groote T,
et al. Renin-angiotensin-aldosterone system dynamics after targetedblood pressure control using angiotensin II or norepinephrine in
cardiac surgery: mechanistic randomised controlled trial. Br J Anaesth.
2023;131:664–72.
Sadjadi M, von Groote T, Weiss R, Strauß C, Wempe C, Albert F, et al. A
pilot study of renin-guided angiotensin-II infusion to reduce kidney stress

Page 8 of 8

after cardiac surgery. Anesth Analg. 2024. https://​doi.​org/​10.​1213/​ANE.​
00000​00000​006839.
40. Khanna AK. Tissue perfusion and prognosis in the critically Ill-is renin the
new lactate? Crit Care Med. 2019;47:288–90.

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