Abstract
Background:
Studies in critically ill adults demonstrate associations between serum renin concentrations (a proposed surrogate for renin-angiotensin-aldosterone system dysregulation) and poor outcomes, but data in critically ill children are lacking. We assessed serum renin+prorenin concentrations in children with septic shock to determine their predictive ability for acute kidney injury (AKI) and mortality.
Methods:
Secondary analysis of a multi-center observational study of children aged 1 week to 18 years admitted to 14 PICUs with septic shock and residual serum available for renin+prorenin measurement. Primary outcomes were development of severe persistent AKI (≥KDIGO Stage 2 for ≥48 hours) in the first week and 28-day mortality.
Results:
Among 233 patients, Day 1 median renin+prorenin concentration was 3436 pg/ml (IQR 1452-6567). Forty-two (18%) developed severe persistent AKI and 32 (14%) died. Day 1 serum renin+prorenin predicted severe persistent AKI with an AUROC of 0.75 (95%CI 0.66-0.84, p<0.0001; optimal cutoff 6769 pg/ml) and mortality with an AUROC of 0.79 (95%CI 0.69-0.89, p<0.0001; optimal cutoff 6521 pg/ml). Day 3:Day 1 (D3:D1) renin+prorenin ratio had an AUROC 0.73 (95%CI 0.63-0.84, p<0.001) for mortality. On multivariable regression, Day 1 renin+prorenin >optimal cutoff retained associations with severe persistent AKI (aOR 6.8, 95%CI 3.0-15.8, p<0.001) and mortality (aOR 6.9, 95%CI 2.2-20.9, p<0.001). Similarly, D3:D1 renin+prorenin >optimal cutoff was associated with mortality (aOR 7.6, 95%CI 2.5-23.4, p<0.001).
Conclusions:
Children with septic shock have very elevated serum renin+prorenin concentrations on PICU admission and these concentrations, as well as their trend over the first 72 hours, predict severe persistent AKI and mortality.
Keywords: sepsis, acute kidney injury, pediatrics, mortality, renin
Introduction:
Septic shock is a common diagnosis in the pediatric intensive care unit (PICU) that is associated with morbidity, mortality, and high resource utilization [1–4]. Outcomes are particularly poor in the 20% of children who develop severe acute kidney injury (AKI), which confers up to 5 times increased risk of death compared to children who do not develop severe AKI, and is associated with morbidity and reduced health-related quality of life in survivors [5–7]. Unfortunately, the treatment for septic shock and sepsis-associated AKI remains largely supportive, relying on prompt recognition and treatment of infection with antibiotics, circulatory support with fluid resuscitation and vasoactive medications, and additional organ support like kidney replacement therapy (KRT), as necessary [8]. Thus, significant research efforts have been focused on elucidating methods to identify children at highest risk for sepsis-associated AKI and its sequelae early in PICU admission, with the hope that proactive intervention may mitigate ongoing injury [9–14].
To this end, investigators have leveraged emerging data in adults suggesting presence of renin-angiotensin-aldosterone system (RAAS) dysregulation in the setting of critical illness. This work has identified serum renin concentrations— which are evaluated more feasibly than other components of the complex RAAS pathway [15]— as a predictor of poor outcomes, including AKI [16–19]. Recently, a multicenter study of critically ill adults demonstrated early serum renin concentrations were associated with Major Adverse Kidney Events (MAKE), and persistence of serum renin elevation over time was associated with mortality [16]. Specific to sepsis-associated AKI, a recent single center study demonstrated that plasma renin concentration was associated with poor kidney outcomes, including AKI persistence and need for kidney replacement therapy (KRT) [19]. To date, no data exist regarding typical serum renin concentrations in children with septic shock, nor their associations with AKI development or incidence of mortality.
In this context, we sought to assess for biochemical evidence of RAAS dysregulation on admission and over the first 72 hours of PICU stay for septic shock and examine its association with the development of severe persistent AKI and PICU mortality. We hypothesized that children with septic shock and evidence of more severe RAAS dysregulation at both Day 1 and Day 3 would have a higher incidence of both outcomes of interest.
Materials and Methods:
Study Design and Patient Selection:
We performed a secondary analysis of a prospective, observational study of children aged 1 week to 18 years with septic shock conducted from January 2015 to December 2018 at 14 PICUs across the United States. Septic shock was defined as the presence of 2 or more systemic inflammatory response syndrome (SIRS) criteria secondary to proven or suspected infection with evidence of cardiovascular dysfunction (see Supplementary Methods). The original study protocol (which has been previously published in detail [20]) included serum collection on Day 1 and Day 3, and was reviewed and approved by the Cincinnati Children’s Hospital Medical Center Institutional Review Board (IRB) prior to patient enrollment (Study Number: 2008-0558; Study Title: Genomics of Septic Shock; initial approval 2008, last continuing review approved 5/6/2022). Procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the 1964 Declaration of Helsinki and its later amendments. Importantly, this IRB-approved study protocol includes approval for future secondary analyses of de-identified data. Patients from the original study (n=461) were included in our analyses if they had serum creatinine (SCr) data available, no history of pre-existing kidney disease, and residual serum from Day 1 and Day 3 available for analysis (Supplementary Figure 1).
Measurements:
Samples were analyzed for each patient on Day 1 and Day 3 using a human renin Luminex® assay (R&D Systems Inc., Minneapolis, MN, USA). This assay was selected due to the small volume of residual serum available. However, this assay also measures prorenin, the inactive proenzyme form of renin (typically 5- to 10-fold higher than renin) [21, 22]. As we are unable to distinguish renin from prorenin in these measurements, the values measured represent combined renin and prorenin concentrations (renin+prorenin). A Day 3:Day 1 (D3:D1) renin+prorenin ratio was also calculated for each patient to quantify the trend in serum renin+prorenin concentration over the first 72 hours of septic shock. As part of the original study, the PERSEVERE biomarkers (C-C chemokine ligand 3, granzyme B, heat shock protein 70kDa 1B, interleukin-8 and matrix metallopeptidase 8) were measured from the serum in the first 24 hours of admission, and combined with platelet count to assign a baseline risk of mortality (PERSEVERE-II mortality probability), as previously validated [20, 23]. All other data (clinical and laboratory) were measured as part of clinical care and collected daily (for up to 7 days) as part of the original study protocol. Mortality was tracked for 28 days after enrollment. PICU-free days were calculated by subtracting the number of days in the PICU from a maximum of 28 days; vasoactive-free days were calculated by subtracting the number of days on vasoactives from a maximum of 7 days.
Outcomes and Definitions:
We assessed for an association between Day 1 serum renin+prorenin concentration and D3:D1 renin+prorenin ratio with our primary outcomes of interest: (1) the development of severe, persistent AKI in the first week of PICU stay, and (2) 28-day PICU mortality. Severe persistent AKI was defined as Kidney Disease Improving Global Outcomes (KDIGO) Stage 2 or higher by SCr criteria (≥2x increase in SCr from baseline) lasting for ≥48 hours consecutively [24, 25]. We chose to focus on this specific definition of AKI given its now well-documented association with poor outcomes in children with septic shock [5, 26]. Baseline SCr values were unknown for all patients in the cohort, and thus were imputed using their calculated body surface area (m2) and an eGFR of 120 ml/min per 1.73 m2, as validated in the literature [27, 28].
In addition to the PERSEVERE-II mortality probability, two additional scores were used as surrogates of severity of illness in this study: the Pediatric Risk of Mortality III (PRISM III) score, calculated from data in the first 4 hours of PICU care [29, 30], and the maximum vasoactive-inotropic score (VIS) in the first 24 hours of PICU admission for septic shock [31].
Statistical Analysis:
Data were initially described using medians, interquartile ranges, frequencies and percentages. Comparisons between groups were performed using Wilcoxon rank-sum or Chi-square test, as appropriate. Receiver operator characteristic (ROC) curves were generated and the area under the ROCs (AUROCs) were calculated to assess the predictive performance of Day 1 serum renin+prorenin concentrations and serum renin+prorenin trend (D3:D1 renin) for prediction of both outcomes of interest. A Youden Index was calculated to determine the optimal cutoff to predict each outcome, maximizing both sensitivity and specificity; sensitivities, specificities, positive predictive values (PPV) and negative predictive values (NPV) were then calculated for each outcome using these optimal cutoff values. For regression analyses, Day 1 serum renin+prorenin concentration and D3:D1 renin+prorenin ratios were first transformed to dichotomous variables (i.e., above or below the previously identified optimal cutoff for prediction of each outcome). Multivariable logistic regression was then utilized to assess for the independent association between Day 1 serum renin+prorenin above the optimal cutoff and D3:D1 renin+prorenin above the optimal cutoff with the development of severe persistent AKI and 28-day mortality. Adjustments were made for severity of illness (by PRISM III, VIS and PERSEVERE-II mortality probability) and other significant covariates (p <0.10) identified on bivariate analysis for each outcome. A p-value of <0.05 was considered statistically significant. All statistical analyses were performed using Sigmaplot 14.0 (Systat Software Inc., San Jose, CA, USA) and SAS® 14.0 (SAS Institute, Cary, NC, USA)
Results:
Cohort Demographics and Clinical Characteristics:
A total of 461 patients were enrolled in the original study. After exclusion of patients with missing SCr data (n=36), pre-existing kidney disease (n=46), and those without available Day 1 and Day 3 serum for renin+prorenin analyses (n=146), a total of 233 patients were included (Supplementary Figure 1).
On Day 1, the median renin+prorenin concentration for the cohort was 3436 pg/ml (IQR 1452-6567). Among 233 patients, 42 (18%) developed severe persistent AKI in the first week of PICU stay. Table 1 provides demographic and clinical characteristics of the study cohort by the presence or absence of severe persistent AKI. There were no differences in age, sex, need for mechanical ventilation on Day 1, or cumulative PICU fluid balance at Day 3 between the two groups; however, those with severe persistent AKI had higher PRISM III and VIS on the day of PICU admission and were more likely to have fungal sepsis. Severe persistent AKI was associated with increased KRT use, fewer 7-day vasoactive-free days, fewer 28-day PICU-free days and increased risk for mortality (Table 1).
Table 1:
Clinical data and outcomes by the presence or absence of Day 1-7 severe persistent acute kidney injury.
| Variable | All Patients | No Severe Persistent AKI |
Severe Persistent AKI |
p-value |
|---|---|---|---|---|
|
| ||||
| N (% cohort) | 233 | 191 (82) | 42 (18) | -- |
|
| ||||
| Sex, n (% male) | 109 (47) | 91 (48) | 18 (43) | 0.57 |
|
| ||||
| Age, years | 5 (1.6,9.3) | 5 (1.6,9.5) | 4.1 (1.4,9.3) | 0.72 |
|
| ||||
| PRISM III | 11 (8,16) | 10.4 (7,15) | 16 (10.9,21.6) | <0.001 |
|
| ||||
| PERSEVERE-II Mortality Probability | 0.0190 (0.007,0.189) |
0.007 (0.007,0.189) |
0.189 (0.019,0.444) |
<0.001 |
|
| ||||
| Causative Organism | ||||
| Gram positive, n (%) | 57 (24.5) | 47 (24.6) | 10 (24) | 0.91 |
| Gram negative, n (%) | 61 (26) | 51 (26.7) | 10 (24) | 0.70 |
| Viral, n (%) | 21 (9.0) | 17 (8.9) | 4 (9.5) | 0.90 |
| Fungal, n (%) | 8 (3.5) | 4 (2.1) | 4 (9.5) | 0.017 |
| None, n (%) | 86 (37) | 72 (37.7) | 14 (33) | 0.60 |
|
| ||||
| D1 Vasoactives, n (%) | 213 (91) | 171 (90) | 42 (100) | 0.028 |
|
| ||||
| D1 VIS | 15 (5.5,30) | 12.5 (5,30) | 22.8 (12.8,48.5) |
<0.001 |
|
| ||||
| D1 Mechanical Ventilation, n (%) | 174 (75) | 138 (72) | 36 (86) | 0.069 |
|
| ||||
| D1 Renin+Prorenin, pg/ml | 3436 (1452,6567) |
2790 (1345,5149) |
8140 (3490,24251) |
<0.001 |
| Above Optimal Cutoff, n (%)a | 55 (24) | 30 (16) | 25 (60) | <0.001 |
|
| ||||
| D3 Renin+Prorenin, pg/ml | 1617 (848,3944) |
1384 (729,2841) |
7514 (1878,21417) |
<0.001 |
|
| ||||
| D3:D1 Renin+Prorenin Ratio | 0.52 (0.32,0.94) |
0.49 (0.31,0.80) |
0.89 (0.41,1.25) |
0.01 |
| Above Optimal Cutoff, n (%)b | 76 (33) | 52 (27) | 24 (57) | <0.001 |
|
| ||||
| D3 Cumulative Fluid Balance (%) | 5.3 (0.8,12.0) | 5.2 (1.3,11.7) | 5.5 (−0.4,13.2) | 0.67 |
|
| ||||
| D1-7 KRT, n (%) | 27 (11.6) | 2 (1.0) | 25 (60) | <0.001 |
|
| ||||
| 7-Day Vasopressor-Free Days | 4 (2,5) | 4 (2,6) | 3 (0,4) | <0.001 |
|
| ||||
| 28-Day PICU-Free Days | 19 (5,23) | 19 (9,23) | 2 (0,19) | <0.001 |
|
| ||||
| 28-Day Mortality, n (%) | 32 (14) | 14 (7.3) | 18 (43) | RR 5.9 (3.2-10.8, p<0.001) |
Continuous variables reported as median (IQR); RR- relative risk (95% confidence interval, p-value)
AKI=acute kidney injury; VIS= vasoactive-inotropic score; KRT= kidney replacement therapy
Optimal cutoff for Day 1 serum renin+prorenin= 6769 pg/ml
Optimal cutoff for Day 3:Day 1 renin+prorenin ratio= 0.71
Serum Renin+Prorenin Concentrations for Prediction of Severe Persistent AKI:
Patients with severe persistent AKI had higher serum renin+prorenin concentrations on Day 1 and Day 3, as well as higher D3:D1 renin+prorenin ratios (Table 1). Day 1 serum renin+prorenin performance for severe persistent AKI prediction had an AUROC of 0.75 (95%CI 0.66-0.84, p<0.0001), and an optimal cutoff of 6769 pg/ml was identified to maximize both sensitivity (60%, 95%CI 43-74) and specificity (84%, 95%CI 78-89) (PPV: 45%, 95%CI 32-59; NPV: 90%, 95%CI 84-94; Youden Index=0.44) (Table 2). Patients with Day 1 serum renin+prorenin concentration above the 6769 pg/ml threshold had higher risk of requiring KRT and 28-day mortality, as well as fewer 7-day vasoactive-free and 28-day PICU-free days (Table 3). The D3:D1 renin+prorenin ratio performance for severe persistent AKI prediction had an AUROC of 0.63 (95%CI 0.53-0.73, p=0.01), and an optimal cutoff of 0.71 with sensitivity of 57% (95%CI 41-72) and specificity of 73% (95%CI 66-79) (Youden Index=0.30) (Table 2). After adjustment for significant covariates identified on univariable analysis (Table 1), both Day 1 renin+prorenin concentration above 6769 pg/ml and a D3:D1 renin+prorenin ratio above 0.71 were associated with the development of severe persistent AKI in the first week of PICU stay (Table 4).
Table 2:
Test characteristics of Day 1 serum renin+prorenin concentration and Day 3:Day 1 renin+prorenin ratio for prediction of Day 1-7 severe persistent acute kidney injury and 28-day mortality.
| Outcome Predicted Day 1-7 Severe Persistent AKI |
Day 1 Serum Renin+Prorenin Optimal Cutoff= 6769 pg/ml |
D3:D1 Renin+Prorenin Ratio Optimal Cutoff= 0.71 |
|---|---|---|
|
| ||
| AUROC (95%CI) | 0.75 (0.66-0.84) | 0.63 (0.53-0.73) |
| Sensitivity | 60 (43-74) | 57 (41-72) |
| Specificity | 84 (78-89) | 73 (66-79) |
| Positive predictive value | 45 (32-59) | 32 (22-43) |
| Negative predictive value | 90 (84-94) | 89 (82-93) |
|
| ||
| 28-day Mortality | Optimal Cutoff= 6521 pg/ml | Optimal Cutoff= 0.78 |
|
| ||
| AUROC (95%CI) | 0.79 (0.69-0.89) | 0.73 (0.63-0.84) |
| Sensitivity | 66 (47-81) | 69 (50-83) |
| Specificity | 81 (74-86) | 76 (69-81) |
| Positive predictive value | 35 (20-42) | 31 (25-37) |
| Negative predictive value | 94 (89-97) | 94 (89-97) |
Test characteristics reported using optimal cutoff for each test and outcome. All values except AUROC reported as % (95%CI). AKI- acute kidney injury; AUROC- area under the receiver operating curve; CI- confidence interval
Table 3:
Clinical data and outcomes by Day 1 serum renin+prorenin concentration above or below the optimal threshold to predict severe persistent acute kidney injury.
| Variable | Day 1 Renin+Prorenin <6769 pg/ml |
Day 1 Renin+Prorenin >6769 pg/ml |
p-value |
|---|---|---|---|
| N (% cohort) | 178 (76) | 55 (24) | -- |
| Sex, n (% male) | 88 (49) | 21 (38) | 0.14 |
| Age, years | 5.5 (1.8,9.6) | 2.7 (0.8,9.0) | 0.09 |
| PRISM III | 11 (8,15) | 13 (8,18) | 0.08 |
| D1 Vasoactives, n (%) | 161 (90) | 52 (95) | 0.34 |
| D1 VIS | 12.5 (5,28.8) | 21 (10,42) | 0.005 |
| D1-7 Severe Persistent AKI, n (%) | 17 (10) | 25 (45) | RR 4.8 (2.8-8.1, p<0.001) |
| D1-7 KRT, n (%) | 11 (6.2) | 16 (29) | RR 4.7 (2.4-9.5, p<0.001) |
| 7-Day Vasoactive-Free Days | 5 (2.8,6) | 3 (0,4) | <0.001 |
| 28-day PICU-Free Days | 19 (10.8,23) | 6 (0,20) | <0.001 |
| 28-Day Mortality, n (%) | 12 (6.7) | 20 (36) | RR 5.4 (2.8-10.3, p<0.001) |
Continuous variables reported as median (IQR); RR- relative risk (95% confidence interval, p-value)
VIS-vasoactive-inotropic score; KRT- kidney replacement therapy; Severe Persistent AKI: ≥KDIGO stage 2 AKI present for >48h consecutively
Table 4:
Multivariable logistic regression testing for an association between significant variables identified on bivariate analysis and outcomes.
| Outcome | Variable | aOR | 95% CI | p-value |
|---|---|---|---|---|
|
| ||||
| Day 1-7 Severe Persistent AKI | PRISM III | 1.06 | 1.0-1.1 | 0.062 |
| PERSEVERE-IIa | 1.37 | 1.1-1.8 | 0.016 | |
| Day 1 VIS | 1.0 | 0.99-1.02 | 0.38 | |
| Day 1 Renin+Prorenin > Optimal Cutoffb | 6.8 | 3.0-15.8 | <0.001 | |
| D3:D1 Renin+Prorenin Ratio > Optimal Cutoffc | 2.4 | 1.1-5.7 | 0.036 | |
|
| ||||
| 28-day Mortality | PRISM III | 0.99 | 0.92-1.06 | 0.80 |
| PERSEVERE-IIa | 1.64 | 1.2-2.3 | 0.003 | |
| No. of Organ Failures | 2.1 | 1.1-4.0 | 0.032 | |
| Day 1 VIS | 1.0 | 0.99-1.0 | 0.87 | |
| Day 1 Renin+Prorenin > Optimal Cutoffd | 6.9 | 2.2-20.9 | <0.001 | |
| D3:D1 Renin+Prorenin Ratio > Optimal Cutoffe | 7.6 | 2.5-23.4 | <0.001 | |
AKI= acute kidney injury; VIS= vasoactive-inotropic score; aOR= adjusted odds ratio; CI= confidence interval
The raw PERSEVERE-II mortality probability was transformed by a factor of 10 for the logistic regression analyses
Optimal cutoff for Day 1 serum renin+prorenin= 6769 pg/ml
Optimal cutoff for Day 3:Day 1 renin+prorenin ratio= 0.71
Optimal cutoff for Day 1 serum renin+prorenin= 6521 pg/ml
Optimal cutoff Day 3:Day 1 renin+prorenin ratio= 0.78
Serum Renin+Prorenin Concentrations for Prediction of 28-day Mortality:
Similarly, patients who died by Day 28 (n=32, 14% of cohort) had higher serum renin+prorenin concentration on Day 1 (median 10904 pg/ml [IQR 4722,34520] vs. 2859 pg/ml [IQR 1359,5295], p<0.001) and Day 3 (median 13300 pg/ml [IQR 4578,26109] vs. 1384 pg/ml [IQR 734,2934], p<0.001), and higher D3:D1 renin+prorenin ratio (median 1.02 [IQR 0.57,1.8] vs. 0.48 [IQR 0.3,0.75], p<0.001) (Supplementary Table 1). Day 1 serum renin+prorenin performance for 28-day mortality prediction had an AUROC of 0.79 (95%CI 0.69-0.89, p<0.0001), and an optimal cutoff of 6521 pg/ml, with sensitivity of 66% (95%CI 47-81) and specificity of 81% (95%CI 74-86) (PPV: 35%, 95%CI 20-42; NPV: 94%, 95%CI 89-97); Youden Index=0.51) (Table 2). D3:D1 renin+prorenin ratio was also predictive of mortality, with an AUROC of 0.73 (95%CI 0.63-0.84, p<0.001), and an optimal cutoff of 0.78, with sensitivity of 69% (95%CI 50-83) and specificity of 76% (95%CI 69-81) (Youden Index=0.49) (Table 2). After adjustment for significant covariates identified on bivariate analysis (Supplementary Table 1), both having Day 1 renin+prorenin concentration above 6521 pg/ml and D3:D1 renin+prorenin ratio above 0.78 were associated with 28-day mortality (Table 4).
Discussion:
In this secondary analysis of a large, prospective, multicenter study of critically ill children with septic shock, we found that serum renin+prorenin concentrations were modestly predictive of both severe persistent AKI development in the first week of PICU admission and 28-day mortality. Additionally, persistence of renin+prorenin elevation at Day 3 (as quantified by D3:D1 renin+prorenin ratio) was also predictive of 28-day mortality. After adjustment for potential confounders including severity of illness and vasoactive burden, having a Day 1 serum renin+prorenin concentration above the optimal threshold was the strongest predictor of severe persistent AKI in this cohort, while a D3:D1 renin+prorenin ratio above the optimal threshold was the strongest predictor of 28-day mortality. Finally, in this first study to examine serum renin+prorenin concentrations in children with septic shock, median Day 1 values were very elevated at 3426 pg/ml, nearly 20 times higher than direct renin concentrations reported in critically ill adults and 60 times higher than the direct renin upper limit of normal (59 pg/ml) [17]. While co-measured prorenin (typically 5- to 10-fold higher than renin) certainly contributes to this elevation, these values are still higher than expected when compared to similar studies in adults [21, 22].
These data add to the growing body of literature in adult patients demonstrating similar associations between serum renin concentrations, mortality, and adverse kidney outcomes in critically ill patients [16–18, 32, 33]. While the exact pathophysiologic process responsible for these associations is not clear, renin is an upstream molecule in the RAAS (Figure 1) which is now increasingly recognized to be deranged in critical illness. In the setting of septic shock, it is postulated that endothelial injury results in ACE dysfunction or deficiency, reduced conversion of angiotensin I to angiotensin II, and resultant angiotensin II deficiency that exacerbates vasodilatory shock, alters glomerular perfusion pressure, and upregulates renin (Figure 1) [17, 34, 35]. In support of this hypothesis, Bellomo and colleagues were able to demonstrate in a post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) Study that adults with catecholamine-resistant vasodilatory shock had high concentrations of serum renin, and that those concentrations were (1) correlated to high angiotensin I/angiotensin II ratios (which were used as a surrogate for ACE activity) and (2) decreased in response to exogenous angiotensin II administration [17]. In this same study, patients with serum renin concentrations above the population median had higher rates of AKI and mortality, and even more intriguing, risk of each of these outcomes was reduced by receipt of synthetic angiotensin II [17, 36]. Given our findings demonstrating similar associations between renin+prorenin elevation and outcomes in children with septic shock, further study is warranted to elucidate if angiotensin II may be particularly beneficial in this population, especially in those with AKI.
Figure 1: Proposed Mechanism of Renin-Angiotensin-Aldosterone System Derangement in the Setting of Septic Shock.
Under normal circumstances, inactive prorenin undergoes proteolytic activation to renin in the kidney, where active renin is stored and released immediately upon stimulation of the juxtaglomerular apparatus. In the setting of septic shock and associated endothelial dysfunction and/or damage, angiotensin-converting enzyme (ACE) function is proposed to be impaired, resulting in acutely decreased production of angiotensin II, decreased production of aldosterone, and resultant increase in serum renin concentrations secondary to release of active enzyme. While proteolytic activation of prorenin to renin is also ongoing, this process is influenced more by chronic stimuli as opposed to acute stimuli.
Consistent with adult data, our results also suggest that renin+prorenin kinetics are important, as decreasing values over the first three days of PICU admission were associated with better outcomes. In this cohort, patients who did not develop either primary outcome of interest had renin+prorenin concentrations decrease by 50% over the first 72 hours, while those who died or developed severe persistent AKI had persistent elevation of renin+prorenin during that timeframe (Table 1 and Supplementary Table 1). While it is possible that this decrease represents improvement in RAAS derangement which subsequently lead to better outcomes, it is also important to note that renin has other direct effects that may impact outcomes in this patient population. In particular, renin binds the (pro)renin receptor on leukocytes resulting in the production of proinflammatory cytokines, which can also exacerbate vasodilatory shock and end organ injury in the setting of sepsis [37]. Additionally, renin release can increase rapidly in response to acute stimuli such as hypotension, which could be a significant driver of both elevated renin+prorenin concentrations and poor outcomes in this population [21, 22]. Though we have attempted to account for severity of hypotension using vasoactive burden by VIS as a surrogate, this dataset lacks the granularity to correlate degree of hypotension for age with renin+prorenin concentrations directly. Ultimately, while the mechanism responsible for the association between decreasing renin+prorenin concentrations and improved outcomes is likely multifactorial, it appears that children with septic shock demonstrate similar associations between renin+prorenin kinetics and outcomes as their adult counterparts.
While substantially more work is needed, our findings suggest that renin may be an important biomarker for both prognostic (i.e. prediction of outcomes) and predictive (i.e. guiding targeted therapy) enrichment for children with septic shock, particularly those with AKI. While its predictive characteristics for severe persistent AKI are modest, its performance may be enhanced by guided measurement in patients deemed high risk by validated tools like the Renal Angina Index, which is an area of future study [9, 38]. However, perhaps more intriguing is the potential for renin to aid in discerning a specific underlying AKI subphenotype (i.e., angiotensin II deficient) and guide a patient-specific therapy (i.e., exogenous angiotensin II) to improve outcomes in children with septic shock and associated AKI [39]. Given the degree of renin+prorenin elevation seen in our cohort, we believe that high-quality prospective studies similar to those conducted in adults are needed to test these hypotheses in children [17, 36].
This study has several strengths. Importantly, this is the first study to examine serum renin+prorenin concentrations in children with septic shock. The cohort is large and multicenter, enhancing the generalizability of the results. Detailed clinical data were available for study patients, allowing for consideration of and adjustment for multiple markers of illness severity, including the validated, pediatric sepsis-specific PERSEVERE-II mortality probability [20]. Finally, the availability of serum from Day 1 and Day 3 allowed us to assess the impact of renin+prorenin kinetics on outcomes as opposed to just one static measurement alone, a concept that is hugely important in critical illness. The importance of the ability to assess changes in renin+prorenin concentrations over time is also highlighted by the fact that these changes are more likely to be reflective of changes in renin concentrations, as prorenin release is continuous and often unaltered by acute stimuli (i.e., hypotension in the setting of septic shock) [21].
Our work also has important limitations. Most notably, the inability to use a direct renin assay makes direct comparison to the existing literature in adults challenging and represents an important gap in knowledge that should be addressed in future studies, especially with increasing clinical availability of timely direct renin assays. Furthermore, this is a secondary analysis of an observational study, and thus we were limited to de-identified data and specimen collected as part of the original study. Baseline SCr data were not available, forcing us to rely on estimated values for all patients. Finally, we used only SCr-based AKI definitions as urine output data were not reliably collected as part of the original study, raising the possibility that AKI rates were underestimated.
Conclusions:
Children with septic shock have very elevated serum renin+prorenin concentrations on PICU admission, and these concentrations are modestly predictive of severe persistent AKI and mortality. Further work is needed to better identify and characterize RAAS derangement in pediatric septic shock and associated AKI, as it may represent a modifiable target to improve outcomes in these children.
Supplementary Material
Acknowledgements:
The authors would like to acknowledge the late Dr. Hector Wong, the leader of this multicenter study of pediatric septic shock for over a decade, and a mentor to all of us. He was intimately involved in the conceptualization of this project, though tragically passed before the data were analyzed and manuscript was written. The authors would also like to thank Patrick Lahni and Kelli Harmon for technical assistance in the conduct of this study.
Financial Support for Study:
This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (KL2TR001426). The original study was funded by National Institute of General Medical Sciences, R35GM126943 (PI: Hector R. Wong). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Statements and Declarations:
Dr. Fitzgerald is supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (K23DK119463). The remainder of the authors report no financial disclosures or conflict of interest relevant to this work.
References:
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