SCCM Resource Library-Persistent Serum Renin Elevation is Associated With Acute Kidney Injury in Pediatric Septic Shock

Video Transcription

Hello, I'm Natalia Stansky, and I am excited to present to you our research looking at  persistency and renin elevation and its association with acute kidney injury and pediatric septic shock. This is my funding, and I have nothing to disclose.  Sepsis-associated AKI occurs in 20% of children with severe sepsis and is associated with significant morbidity and mortality.  There have now been several studies demonstrating the independent association of sepsis-associated  AKI with mortality in critically ill children and reduced quality of life in those who survive.  However, despite a growing understanding of its consequences, treatments for sepsis-associated AKI remain limited, in large part due to a poor understanding of its pathophysiology  on the individual patient level. As a result, we continue to lack disease-modifying therapies that are sorely needed to improve  outcomes, relying solely on supportive care measures alone. Recently, emerging data in adults demonstrate the potential role of the renin-angiotensin-aldosterone  system in sepsis-associated AKI pathophysiology. A post-hoc analysis of the APHO3 trial demonstrated that patients with vasodilatory shock and  elevated renin levels had higher rates of severe AKI. Furthermore, patients from the same study with AKI and elevated renin levels had higher  rates of renal recovery if they received angiotensin-2 therapy. Why might that be? Recall that under normal circumstances, your body uses renin to convert angiotensinogen  to angiotensin-1, which is subsequently converted to angiotensin-2 and then aldosterone, both  of which are key regulators of blood pressure both systemically and locally at the level of the glomerulus.  In the setting of severe sepsis endothelial dysfunction, angiotensin-converting enzyme,  which is housed predominantly in the vasculature, has reduced function and thus decreased production of angiotensin-2 occurs.  The result is an upstream increase in renin in response, which has been theorized to identify patients who may be most likely to benefit from exogenous angiotensin-2 therapy.  These concepts have not yet been explored in children. We hypothesize that children with septic shock would have elevated levels of renin on presentation  predominantly because they would have high rates of endothelial injury and dysfunction. Additionally, we believe that children with endothelial dysfunction have higher rates  of AKI and thus elevated renin levels would be associated with the development of severe AKI and provision of kidney replacement therapy, or KRT.  To test these hypotheses, we performed a secondary analysis of a prospective multicenter study of 379 children admitted to the PICU with septic shock from 2015 to 2019.  From these patients, a subset of 69 were chosen for an exploratory pilot study based on the availability of day 1 and day 3 serum samples, as well as the representative incidence  of day 3 severe AKI. Serum renin concentrations were measured on day 1 and day 3 by Luminex assay, and the  individual patient trend in serum renin was quantified using a day 3 to day 1 renin ratio. Day 1 and day 3 renin levels, as well as their trend by day 3 to day 1 renin ratios, were  evaluated for association with our primary outcomes of day 3 severe sepsis-associated AKI, which is a doubling of creatinine above baseline or worse, and provision of kidney  replacement therapy in the first week of ICU stay. Finally, we performed risk-stratified analyses to assess for the additive value of renin  levels when used in concert with the previously validated renal angina index and the recently derived Persevere 2 AKI prediction model.  For those who are unfamiliar, briefly, the renal angina index is a validated pediatric AKI risk prediction tool for patients admitted to the ICU.  It multiplies a risk criteria score outlined in orange and an injury strata score outlined in blue to get a composite score ranging from 1 to 40.  Patients with a score of 8 or higher are said to have renal angina and are at high risk for severe AKI three days later.  Similarly, the Persevere 2 AKI prediction model is a recently derived tool specifically for children with septic shock.  The Persevere biomarkers are validated biomarkers of pediatric septic shock that can be measured  in the first 24 hours to predict mortality, also known as the Persevere 2 mortality probability.  To derive this AKI prediction model, classification and regression tree modeling was utilized to create a decision tree incorporating AKI severity on presentation, the Persevere 2  mortality probability, and the individual Persevere biomarkers themselves to predict which patients would develop severe AKI day three.  Patients in the high-risk terminal nodes noted in red are predicted to have severe AKI by this model, while those in low-risk terminal nodes indicated in green are predicted not  to have severe AKI. Moving on to results, first, we found that children with septic shock had extremely high serum renin levels on presentation.  This chart outlines the basic demographic characteristics of the pilot cohort. Overall, it was a fairly sick cohort with a medium PRISM score of 14, high rates of  both severe AKI and KRT use at 38% and 17%, respectively, and high rates of mortality at 22%.  When we look at the median day one and day three renin levels, we see that they are extremely elevated.  Recall, the median renin level in the adult study cited previously was only 59 picograms per ml.  Additionally, it appeared that most patients had renin levels that downtrended over the course of the first three days, with a median day three to day one renin ratio of about 0.5.  Second, we showed that persistent renin elevation is associated with both severe AKI and KRT are primary outcomes of interest.  Looking first at patients by the presence or absence of severe AKI at day three, we see that there are no significant differences in day one renin level between these groups.  Median day three renin levels were higher in those with severe AKI, and the individual day three to day one renin ratio was closer to one in patients who developed AKI, indicating  a failure of downtrend from day one values. Similarly, in patients who received KRT, while there were no significant differences in day  one renin values compared to those who did not require KRT, day three renin values were also significantly higher in these patients.  Furthermore, day three to day one renin ratios indicated a slight increase in renin levels over the first three days in patients who required KRT, while those who did not require  KRT had a clear downtrend with a day three to day one renin ratio of 0.5. Finally, we found that renin trend, as indicated by individual patient day three to day one  renin ratio, could help refine AKI prediction using existing tools. First, when examining patients broken down by risk category using the Persevere 2 AKI  prediction model, we see that high-risk patients who did not develop AKI, or false positives, could be distinguished from true positives by a clear downtrend in renin from day one  to day three. Additionally, the few low-risk patients who went on to develop AKI, or false negatives, could be distinguished from true negatives by a clear uptrend in renin level.  Similarly, in patients with renal angina predicted to have AKI by their renal angina index, true  positives were distinguished from false positives by an elevated day three to day one renin ratio, signifying a persistent elevation of renin from day one to day three.  In conclusion, children with septic shock have renin levels that are more than 80 times higher than adults on presentation.  Persistent renin elevation is associated with severe sepsis-associated AKI and provision of KRT, and may discriminate between true positives and false positives in high-risk  patients identified using existing AKI predictive tools. Similar to adult studies, these data suggest that involvement of the renin angiotensin  aldosterone system in sepsis-associated AKI pathophysiology is possible and should be further explored.  Importantly, renin may be a predictive enrichment target to guide angiotensin II therapy and improve outcomes.  In terms of limitations and future directions, this was obviously a small pilot study that needs to be expanded, and currently we have work ongoing to build upon this pilot cohort.  And as has been done in adults, further work is needed to tie the elevation in serum renin levels directly to markers of endothelial dysfunction, and to evaluate the use of renin  as a predictive enrichment tool to guide precision vasoactive management with angiotensin II.  I'd like to thank my mentors listed here on this slide, as well as the Cincinnati Children's  Hospital Center for Acute Care Nephrology, of which I am a co-director, my funding through the University of Cincinnati CCTST, and then also Kelly Harmon and Patrick Lawney of the  Wong Lab for their assistance with this study. With that, I'm happy to take any questions.

Video Summary

The research presented by Natalia Stansky explores the association between persistency and renin elevation with acute kidney injury (AKI) in pediatric septic shock. Sepsis-associated AKI occurs in 20% of children with severe sepsis and is linked with morbidity and mortality. The study investigates the potential role of the renin-angiotensin-aldosterone system in the pathophysiology of sepsis-associated AKI, focusing on renin levels as a predictive enrichment target for angiotensin II therapy. The findings suggest that persistent renin elevation is associated with severe AKI and provision of kidney replacement therapy. Further research is needed to validate these results and explore treatment options for sepsis-associated AKI in children.

Asset Subtitle

Sepsis, Renal, Pediatrics, 2022

Asset Caption

INTRODUCTION/HYPOTHESIS: Sepsis-associated acute kidney injury (SA-AKI) is associated with poor outcomes in critically ill children. The pathophysiology of SA-AKI is poorly understood, limiting treatment strategies. Adult studies highlight the potential role of the renin-angiotensin-aldosterone system (RAAS), by correlating renin levels >59 pg/ml with development of AKI. This concept has not yet been examined in children. METHODS: A secondary analysis of 379 children admitted to a PICU from a multi-center study of pediatric septic shock. A subset of 69 patients were selected based on availability of Day1 (D1) and Day3 (D3) serum samples, and the presence or absence of D3 severe SA-AKI (primary outcome, defined as ≥KDIGO stage 2). Serum renin concentrations were measured on D1 and D3 by Luminex® assay; these values, and their trend (D3:D1 ratio), were assessed for associations with SA-AKI and provision of renal replacement therapy (RRT). Risk stratified analyses were also performed using the previously validated Renal Angina Index (RAI) and the recently derived PERSEVERE-II Model. RESULTS: 26/69 (38%) subjects developed D3 severe SA-AKI and 12 (17%) received RRT. Median D1 renin value was 4751 pg/ml (IQR 1926-10307), with no D1 differences between subjects with vs. without SA-AKI or RRT. Median D3 renin values were higher for those with D3 severe SA-AKI (5250 pg/ml vs. 2153 pg/ml, p=0.035) and who required RRT (7514 pg/ml vs. 2221 pg/ml, p=0.014). These subjects also had higher median D3:D1 renin ratios (D3 severe SA-AKI: 0.99 vs 0.41, p=0.003; RRT: 1.1 vs. 0.51, p=0.014). In patients at high risk for D3 severe SA-AKI by either the RAI or PERSEVERE-II Model, the median D3:D1 renin ratio discriminated between true positives (those who developed severe SA-AKI) and false positives (those who did not) (RAI: 0.99 vs 0.41, p=0.016; PERSEVERE-II: 0.95 vs 0.41, p=0.023). CONCLUSIONS: Children with septic shock have very elevated renin levels on presentation, and persistent elevation at D3 is associated with severe SA-AKI and provision of RRT. This persistence also discriminates between true positives and false positives in high-risk patients identified by existing SA-AKI predictive tools. These data suggest a potential role of RAAS in SA-AKI pathophysiology that should be further explored.

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Knowledge Area Renal

Knowledge Area Pediatrics

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Tag Shock

Tag Renal

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Year 2022

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renin elevation

acute kidney injury

sepsis-associated AKI

pediatric septic shock

angiotensin II therapy

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Renal

Pediatrics

Shock

Renal

Pediatrics

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2022

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