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Renin as a Marker of Tissue-Perfusion and Prognosis in Critically Ill Patients*

Gleeson, Patrick J., MB BAO BCh, MSc1–3; Crippa, Ilaria Alice, MD1; Mongkolpun, Wasineenart, MD1; Cavicchi, Federica Zama, MD1; Van Meerhaeghe, Tess, MD1; Brimioulle, Serge, MD, PhD1,4; Taccone, Fabio Silvio, MD, PhD1,4; Vincent, Jean-Louis, MD, PhD1,4; Creteur, Jacques, MD, PhD1,4

doi: 10.1097/CCM.0000000000003544
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Objectives: To characterize renin in critically ill patients. Renin is fundamental to circulatory homeostasis and could be a useful marker of tissue-perfusion. However, diurnal variation, continuous renal replacement therapy and drug-interference could confound its use in critical care practice.

Design: Prospective observational study.

Setting: Single-center, mixed medical-surgical ICU in Europe.

Patients: Patients over 18 years old with a baseline estimated glomerular filtration rate greater than 30 mL/min/1.73 m2 and anticipated ICU stay greater than 24 hours. Informed consent was obtained from the patient or next-of-kin.

Interventions: Direct plasma renin was measured in samples drawn 6-hourly from arterial catheters in recumbent patients and from extracorporeal continuous renal replacement therapy circuits. Physiologic variables and use of drugs that act on the renin-angiotensin-aldosterone system were recorded prospectively. Routine lactate measurements were used for comparison.

Measurements and Main Results: One-hundred twelve arterial samples (n = 112) were drawn from 20 patients (65% male; mean ± SD, 60 ± 14 yr old) with septic shock (30%), hemorrhagic shock (15%), cardiogenic shock (20%), or no circulatory shock (35%). The ICU mortality rate was 30%. Renin correlated significantly with urine output (repeated-measures correlation coefficient = –0.29; p = 0.015) and mean arterial blood pressure (repeated-measures correlation coefficient = –0.35; p < 0.001). There was no diurnal variation of renin or significant interaction of renin-angiotensin-aldosterone system drugs with renin in this population. Continuous renal replacement therapy renin removal was negligible (mass clearance ± SD 4% ± 4.3%). There was a significant difference in the rate of change of renin over time between survivors and nonsurvivors (–32 ± 26 μU/timepoint vs +92 ± 57 μU/timepoint p = 0.03; mean ± SEM), but not for lactate (–0.14 ± 0.04 mM/timepoint vs +0.15 ± 0.21 mM/timepoint; p = 0.07). Maximum renin achieved significant prognostic value for ICU mortality (receiver operator curve area under the curve 0.80; p = 0.04), whereas maximum lactate did not (receiver operator curve area under the curve, 0.70; p = 0.17).

Conclusions: In an heterogeneous ICU population, renin measurement was not significantly affected by diurnal variation, continuous renal replacement therapy, or drugs. Renin served as a marker of tissue-perfusion and outperformed lactate as a predictor of ICU mortality.

1Department of Intensive Care, Cliniques Universitaires de Bruxelles-Hôpital Erasme, Brussels, Belgium.

2Immunoreceptors and Renal Immunopathology Laboratory, INSERM U1149, Université Diderot, Paris, France.

3Division of Nephrology, Royal College of Physicians of Ireland, Dublin, Republic of Ireland.

4Faculté de Médecine, Université Libre de Bruxelles, Brussels, Belgium.

*See also p. 288.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Supported, in part, by the Irish Nephrology Society “Amgen Bursary”, Dublin, Republic of Ireland.

Dr. Gleeson received funding from Irish Nephrology Society (INS), who in turn, received the money from Amgen via the INS Amgen Research Bursary grant; he had no direct dealings with Amgen, and Amgen has no involvement in the study. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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Optimizing tissue-perfusion and oxygen delivery to cells is central to the management of patients with circulatory shock (1). Mean arterial blood pressure (MAP) has long been used as an indicator of tissue-perfusion. However, MAP does not necessarily reflect blood-flow through the microcirculation, and microcirculation dysfunction can cause inadequate oxygen delivery despite normal MAP (2).

Blood lactate and central venous oxygen saturation (ScvO2) are used as markers of tissue-perfusion adequacy (3–5). In sepsis, using lactate to guide early resuscitation has been shown to improve mortality (6). However, the use of lactate to diagnose and guide management in circulatory shock has its limitations: lactate can increase during aerobic metabolism and may be influenced by medications (5 , 7). When high lactate does reflect inadequate tissue-perfusion it is a late marker, as cells have already resorted to anaerobic metabolism. Interpretation of ScvO2 is complicated by its U-shaped distribution with respect to cellular oxygen delivery (1 , 3 , 5). ScvO2 guided resuscitation does not improve outcome in sepsis (8–10). Identifying a more sensitive and specific marker of tissue-perfusion could allow earlier identification of circulatory failure and more refined resuscitation.

The renin-angiotensin-aldosterone system (RAAS) is fundamental to circulatory homeostasis and has been evolutionarily conserved over hundreds of millions of years (11). Renin is the primary driving force in this system and is secreted in response to decreased tissue-perfusion, sympathetic activation, and hypoxic metabolism (12–14). Renin is routinely measured in clinical practice to investigate hypertension but has not been well characterized in acute circulatory failure. There are some issues that could encumber its use in critical care practice: 1) renin has a diurnal variation in healthy subjects (15), 2) its molecular weight (~40 kDa) is at the threshold for removal by hemofiltration (16 , 17), and 3) renin production could be affected by commonly used medications including beta-agonists, RAAS blockers, and furosemide (18–21).

We prospectively characterized renin in an ICU population to determine if it performs well as a marker of tissue-perfusion and if it is interfered with by these predefined factors. In a proof-of-concept analysis, we compared renin with lactate as a predictor of ICU mortality.

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Ethical approval was granted by Hôpital Erasme ethics committee (reference number P2016/267). Patients admitted to a mixed medical-surgical ICU at Hôpital Erasme, Brussels, Belgium, throughout September 2016 were screened (for inclusion and exclusion criteria, see supplementary methods, Supplemental Digital Content 1,

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Sample Collection and Measurements

Patients were in a recumbent position for at least 1 hour before 4 mL of blood was collected from an arterial catheter into an ethylene diamine tetra-acetic acid tube (Vacutainer; Becton Dickinson, Franklin Lakes, NJ); direct plasma renin levels were determined using a chemiluminescent immunoassay (LIAISON; DiaSorin, Vercelli, Italy).

Blood lactate levels were measured regularly (GEM Premier 4000; Instrumentation Laboratory, Bedford, MA) as part of routine care. Renal resistance index was measured once for each patient during the study period at the time of sample collection using bed-side ultrasound and Doppler (LOGIQ S8; GE Healthcare, Chicago, IL).

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Renin Removal by Continuous Renal Replacement Therapy

All circuits used an acrylonitrile 69 hollow fiber (AN69HF) filter (Hospal, Mérignac, France) as part of a Prismaflex system (Gambro, Baxter, Belgium), Samples were collected and analyzed as described in Supplementary Figure 1 (Supplemental Digital Content 2,

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Statistical Analyses

To account for within-subject repeated measures, a mixed-effects model and repeated measures correlation coefficients (Rrm) were used (22). Results from fixed-effects models are reported as the estimated-fixed effect (EFE) with the 95% CI. The rate of change of renin and lactate overtime was used as a summary statistic for each patient and estimated using linear regression (23). Statistics were performed using Prism 7 (GraphPad Software, San Diego, CA), RStudio IDE (RStudio, Boston, MA), and SPSS v21 (IBM, New York, NY) software. See supplementary information (Supplemental Digital Content 1, for power calculations.

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One-hundred twelve arterial blood samples (n = 112) were drawn from 20 patients. There were 260 patients admitted during the study period, of which 186 were screened. Seven women (35%) and 13 men (65%) were included with a mean (±SD) age of 60 (±14) years. Six patients (30%) had septic shock, three patients (15%) had hemorrhagic shock, four patients (20%) had cardiogenic shock, and seven patients (35%) did not have circulatory shock. Patients were enrolled a median (interquartile range [IQR]) of 2 days (1–3.75 d) after admission. The ICU mortality rate was 30% (Supplementary Table 1, Supplemental Digital Content 2, Renin measurement was not possible in two samples, leaving 110 analyzable renin levels.

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An inverse correlation was seen between renin level and hourly urine output in patients who did not receive a loop diuretic (EFE, –40.5; 95% CI, –79.7 to –9.9; ICC, 0.21; p = 0.008) (Fig. 1A). This relationship remained when all samples were included, and the effect of loop diuretics on urine output was adjusted for (EFE, –17.0; 95% CI, –34.5 to –1.8; p = 0.03). Renin correlated inversely with MAP (EFE, –1.6; 95% CI, –2.5 to –0.7; ICC, 0.22; p < 0.001) (Fig. 1B), which remained after adjustment for noradrenaline dose and dobutamine dose (EFE, –1.5; 95% CI, –2.5 to –0.6; p = 0.001).

Figure 1

Figure 1

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Diurnal Variation of Renin

There were 17 sets of renin measurements drawn consecutively at morning, mid-day, evening, and night-time. No significant diurnal variation of direct plasma renin was seen in this population (Friedman statistic 4.8; p = 0.19) (Fig. 1C).

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Medication Interference

Eight patients (40%) received a drug known to act on the RAAS. No interference with renin levels by beta-blockers (EFE, –212.0; 95% CI, –1,619.6 to 76.6; p = 0.18) or ACE inhibitors (ACEi)/ARBs (EFE, 4.7; 95% CI, –151.2 to 175.5; p = 0.92) was detected. Noradrenaline was being administered at collection for 53 samples (48%) and dobutamine for 16 samples (15%). No significant association between renin and noradrenaline dose (EFE, 6.7; 95% CI, –1.8 to 15.9; p = 0.11), or dobutamine dose (EFE, 10.9; 95% CI, –1.7 to 25.0; p = 0.09) was detected in this cohort (curves showing dobutamine dose and concurrent renin levels can be seen in Supplementary Fig. 2, Supplemental Digital Content 2, There was no detectable association between renin and furosemide dose (EFE, 0.23; 95% CI, –0.3 to 0.8; p = 0.39) (Table 1).



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Removal of Renin by Continuous Renal Replacement Therapy

There was no significant difference in renin levels between patients receiving continuous renal replacement therapy (CRRT) or not (EFE, 21.6; 95% CI, –158.7 to 282.8; p = 0.73) (Table 2). The mean (range) total mass removal of renin was 28 µU/kg/min (0–47 µU/kg/min), equating to a percentage mass clearance of 4% ± 4.3% (mean ± SD). Removal was entirely by membrane adsorption during continuous veno-venous hemodiafiltration (Supplementary Table 2, Supplemental Digital Content 2, There was an exponential relationship between circuit blood flow (Qb) and renin removal (R 2 = 0.81), and Qb was the most significant factor in determining rate of renin removal with adjustment for inlet renin concentration and mode of CRRT (regression coefficient, B 0.3; 95% CI, 0.2–0.4; p = 0.01) (Fig. 2A).



Figure 2

Figure 2

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Renal Function

Eleven patients (55%) had acute kidney injury (AKI). Only one of these patients had an intrinsic AKI, without systemic hemodynamic compromise, caused by synergistic nonsteroidal anti-inflammatory drug/ACEi toxicity. There was a significant inverse correlation between renin and creatinine clearance (EFE, –1.2; 95% CI –1.9 to –0.4; p = 0.002). Renin did not associate significantly with urinary sodium or urinary chloride after adjusting for furosemide dose (EFE, 0.2; 95% CI, –0.4 to 0.8; p = 0.57 for sodium and EFE, 0.1; 95% CI, –0.4 to 0.6; p = 0.74 for chloride). There was no significant correlation between renal resistance index and renin (Spearman R = 0.09; p = 0.7) (Supplementary Fig. 3, Supplemental Digital Content 2,; and Table 2). Renin levels were not significantly different between patients with no AKI and those that developed Kidney Disease Improving Global Outcomes (KDIGO) 1 (EFE, 111.1; 95% CI –4,452.1 to 921.5; p = 0.62), KDIGO 2 (EFE, –171.3; 95% CI, –11,372.3 to 1,458.6; p = 0.59), or KDIGO 3 (EFE, 31.3; 95% CI, –1,063.8 to 1,907.1; p = 0.83) AKI. The sole patient with a purely intrinsic cause of AKI had normal renin levels, whereas all patients with prerenal components to their AKI had an elevated renin level (Fig. 2B).

Preexisting hypertension (EFE, 300.0; 95%CI –1,380.8 to 2,402.7; p = 0.93) or chronic kidney disease stage I–III (EFE, 505.0; 95% CI, –251.3 to 12,210; p = 0.45) had no significant bearing on ICU renin levels.

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ICU Mortality

Renin differed significantly between survivors and nonsurvivors after adjusting for dobutamine, noradrenaline, and RAAS drugs (EFE, 1,292.0; 95% CI, 34.7–1,428.7; p = 0.03). The median (IQR; mode) time difference between renin collection and lactate measurement was 36 minutes (15–74; 10). Lactate was significantly different between survivors and nonsurvivors in the same model (EFE, 133.6; 95% CI, 9.9–396.7; p = 0.04). The rate of change of renin over time (mean ± SEM) was significantly different between survivors (–32 ± 26 μU/timepoint) and nonsurvivors (+92 ± 57 μU/timepoint) (p = 0.03), whereas the rate of change of lactate over time was not significantly different between survivors (–0.14 ± 0.04 mM/timepoint) and nonsurvivors (+0.15 ± 0.21 mM/timepoint) (p = 0.07). A renin value above the upper limit of normal (> 40 μU/mL; as defined for supine patients by the hospital laboratory) was a significant marker of ICU mortality at time-points 1, 2, 3, and 4 (Fisher exact test, p = 0.04 at each time-point), whereas a lactate value above the upper limit of normal (> 2 mM) was not a significant marker of ICU mortality at any of those time-points (p = 0.30, 0.56, 0.32, and 0.25 at each time-point, respectively). Renin had 100% (61–100%) sensitivity (95% CI) and 100% (65–100%) negative predictive value (95% CI) for ICU mortality at time-points 1, 2, 3, and 4 (Fig. 3, A and B). Maximum renin discriminated significantly between survivors and nonsurvivors (receiver operator curve area under the curve [ROC AUC], 0.80; p = 0.04), whereas maximum lactate (ROC AUC 0.70; p = 0.17) and Sequential Organ Failure Assessment score on the day of inclusion (ROC AUC 0.73; p = 0.12) did not (Fig. 3C; and Supplementary Fig. 4, Supplemental Digital Content 2, The evolution of renin and lactate measurements in each individual patient over time can be seen in Supplementary Figure 5 (Supplemental Digital Content 2,

Figure 3

Figure 3

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We prospectively characterized renin in critically ill patients and found it to be a useful marker of circulatory function. Its measurement was not interfered with by diurnal variation, medications or CRRT in an ICU population. Moreover, renin was a significant predictor of ICU mortality. Renin levels reached greater than 100-fold the upper limit of normal in nonsurvivors.

Based on its well-established physiologic role, there is a lot of rationale for using renin as a marker of tissue-perfusion and microcirculation function (24). Cells in the macula densa are adapted to stimulate renin release, not only in response to decreased stretch of the renal arteriolar wall (25 , 26) but also in response to decreased chloride delivery to the distal tubule, sympathetic stimulation, and alterations in tissue metabolism (12–14 , 27). In particular, succinate, an intermediate of Krebs’ cycle which increases during hypoxic tissue metabolism, has been found to provoke renin release (28 , 29).

Renin release can be stimulated by beta-agonism (19), so we anticipated an association between dobutamine and renin levels. However, renin levels were seen to rise despite decreasing dobutamine dose, and renin was seen to fall despite the dose of dobutamine remaining constant (Supplementary Fig. 2, Supplemental Digital Content 2, Although we would exercise caution when interpreting levels in patients receiving strong beta-agonists, renin appears useful for following their progress, nevertheless.

We found no significant diurnal variation of direct plasma renin in this ICU population; the lowest set of measurements was taken in the morning, going against physiologic diurnal variation where morning values are highest (15). The half-life of fast-component renin elimination is less than 20 minutes (30–32), so regular monitoring of renin levels throughout the day could track the tissue level effects of therapeutic interventions.

Our findings are in keeping with a retrospective study of direct plasma renin and ICU mortality (33). Chung et al (34) recently reported that plasma renin activity (PRA) is a significant predictor of mortality in sepsis. Here, we measured direct plasma renin rather than PRA. Although these two techniques correlate strongly in healthy subjects (35 , 36), tight levels of agreement have not been shown and they have some important differences. PRA relies on endogenous levels of angiotensinogen, which is influenced by hepatic function and corticosteroids; PRA can also be influenced by endotoxins and is subject to interlaboratory variability (36 , 37). The inflammatory milieu seen in critically ill patients affects endogenous circulating protease inhibitors (38), which could potentially influence the assay. We felt that direct plasma renin would be more reflective of tissue-perfusion and more reproducible in an ICU population.

The renin assay used in this study cross-reacts with enzymatically active prorenin (36). Renin and prorenin molecules are almost identical, and to our knowledge, there is no commercially available, clinical-grade, direct plasma renin assay that does not cross-react with prorenin (36). In healthy subjects, half of circulating prorenin is released from tissues other than the kidney, but less than 2% of it is in the active form detectable by the assay (36 , 39 , 40). Prorenin is not secreted in response to acute hemodynamic alterations, and renin production is amplified much more (50–100 fold) than prorenin (two to three fold) in pathologic states (41). Stimuli lasting days to weeks are required to effect circulating prorenin levels (42). This suggests that renin, rather than prorenin, is the main contributor to the changes seen in measurements across patients, and over time, in the present study.

We found a significant association between renin and creatinine clearance; however, all but one of the patients with AKI also had haemodynamic compromise, and it was probably this, rather than the decreased creatinine clearance itself, that was driving increased renin levels. Having very high renin levels did not preclude normal renal function, and the sole patient with a purely intrinsic AKI (KDIGO 3), caused by toxicity from a combination of ACEi and NSAIDs, had normal renin levels. ACEi can increase renin production, whereas NSAIDs can inhibit it (43), making interpretation of the renin measurement difficult in this case, but renin could potentially serve to differentiate between prerenal and intrinsic causes of AKI.

Doerschug et al (44) have shown that RAAS is activated in sepsis: as tissue oxygen delivery decreased, PRA and angiotensin II increased. In other studies, ACE has been found decreased in sepsis (45), and subsequent lower angiotensin II production has been associated with increased mortality (46). Failure of negative feedback on renin, through RAAS dysfunction, could contribute to increased renin levels in sicker patients. Downstream metabolites of the RAAS, such as angiotensin II, Angiotensin IV, and Angiotensin 1–7, have important effects on inflammation (21 , 47). Binding of renin and prorenin to the (pro)renin receptor stimulates proinflammatory and profibrotic pathways independent of angiotensins (21 , 48 , 49). These data suggest that renin is not just an innocent messenger but could be directly contributing to morbidity and mortality by inducing inflammation and microcirculation dysfunction.

Our study is limited by a small sample size; however, the cohort was heterogenous and representative of a broad range of ICU patients. Other limitations are that patients were enrolled at various points during their ICU admission, and patients with stage IV or V CKD were excluded from the study. We have not demonstrated a direct relationship between renin levels and microcirculation function.

All patients who had a normal renin level survived their ICU stay (100% negative predictive value), and all patients who died in the ICU had elevated renin levels (100% sensitivity). The highest renin value in the study (4,500 µU/mL) was drawn from a patient with cardiogenic shock (not receiving dobutamine at the time of sampling), and the corresponding lactate level was normal (0.7 mMol)—the patient subsequently died. The phenomenon of normal, but relatively higher, lactate levels predicting mortality during the optimization and stabilization phase of ICU care has been reported (50). Renin and lactate levels did not correlate with each other, suggesting that they measure two different (patho)physiologic processes.

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Here, we have validated arterial direct plasma renin as a biomarker of circulatory function in critically ill patients. There is a wealth of biological rationale behind these findings. Further studies should be performed to investigate the utility of renin in guiding the management of critically ill patients.

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We would like to thank Hassan Njimi, PhD (Department of Intensive Care, Hôpital Erasme, Brussels, Belgium), for his advice regarding statistical analysis.

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circadian rhythm; critical care; hemofiltration; microcirculation; renin; shock

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