Renin as a predictive and prognostic biomarker in sepsis-induced hypotension

The National Heart, Lung, and Blood Institute (NHLBI) awarded $243,750 to the University of Pennsylvania on August 25, 2025, under the Cardiovascular Diseases Research program (CFDA 93.837) to conduct a secondary analysis of the NHLBI Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial. The project will deliver research findings evaluating plasma renin as a predictive and prognostic biomarker in sepsis-induced hypotension, with the goal of identifying subphenotypes that may predict patient response to hemodynamic interventions such as fluid administration or vasopressor therapy. The research will test whether baseline plasma renin levels can guide treatment decisions to reduce organ injury and mortality, and whether plasma renin trajectories correlate with patient outcomes in sepsis cases.

This two-year project, concluding July 31, 2027, will be performed in Lexington, Kentucky, and will advance understanding of how the renin-angiotensin system functions as a tissue perfusion marker in sepsis management. The deliverables include scientific analysis and findings that may inform more targeted, phenotype-based therapeutic approaches to sepsis resuscitation, addressing a critical gap in clinical trial efficacy by accounting for the substantial heterogeneity in sepsis presentation and pathophysiology that has previously diluted treatment signals in multicenter trials.

Abstract

Sepsis, the syndrome of life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of death worldwide. A major factor implicated in the failure of sepsis trials is the substantial heterogeneity in clinical presentation and underlying pathophysiological mechanisms that characterize the syndrome, which dilutes signals of efficacy in clinical trials. Identification of subphenotypes is a promising approach to predictive enrichment to help identify which patients may respond differentially to therapeutic interventions in sepsis. Renin, an upstream marker of the renin-angiotensin system (RAS), is a novel biomarker of tissue perfusion that may predict the response to sepsis resuscitation strategies. In addition, renin trajectory may define a novel sepsis subphenotype that advances beyond a static measurement in a single time point and considers trends in plasma renin. Our overall objective is to determine if plasma renin can function as a predictive and prognostic biomarker in sepsis-induced hypotension. Our central hypothesis will be tested by performing a secondary analysis of the nhlbi crystalloid liberal or vasopressors early resuscitation in sepsis (clovers) trial, to evaluate if plasma renin as a marker of tissue perfusion is associated with response to hemodynamic interventions (fluid liberal VS. Fluid conservative), and if sustained activation is associated with mortality. To test this hypothesis, the following specific aims are proposed: (1) test the ability of baseline plasma renin to serve as a predictive biomarker to guide further treatment with intravenous fluids or vasopressor agents to reduce organ injury and mortality in patients presenting with sepsis-induced hypotension, (2) identify and test the ability of plasma renin trajectories to serve as a prognostic marker of mortality in patients with sepsis-induced hypotension, and (3) in patients with sepsis- induced hypotension, assess the association between plasma levels of renin, prorenin, and soluble (pro)renin receptor with markers of endothelial cell dysfunction. This proposal will leverage biospecimens and clinical data from the clovers trial and is submitted in response to RFA-HL-23-018: maximizing the scientific value of the nhlbi biologic biospecimen repository: scientific opportunities for exploratory research (R21). This proposal seeks to advance resuscitation knowledge in nhlbi's lung injury/critical care domain, where evaluation of differences in pathobiology and in response to treatment is a main objective of nhlbi's strategic vision.