Transcriptomic endotypes implicate a unique risk profile for kidney-related outcomes in sepsis

Introduction: Acute kidney injury (AKI) is the most frequent organ dysfunction in critically ill patients with sepsis. Optimal clinical management, including the timing of renal replacement therapy (RRT), is still unclear, caused by the inherent heterogeneity of the syndrome. We sought to apply transcriptomic endotypes to a cohort of critically ill patients with sepsis and associate it with the risk for kidney-related endpoints. Methods: Secondary analysis of a cohort of 200 adult critically ill patients meeting Sepsis-3 criteria. Patients with a prior or immediate need for RRT, decompensated liver cirrhosis, or moribund condition were excluded. Whole-blood RNA (within 12h from ICU admission) was available from 167 patients for Nanostring gene expression analysis of 33 signature mRNAs to allocate patients into one of three pre-described endotypes (inflammopathic (IE), adaptive (AE), coagulopathic (CE)). Clinical outcomes were recorded over a follow-up period of 30d (RRT, persisting AKI, 7/30d all-cause mortality). Results: Fifty-seven patients were allocated to IE, 70 to AE, and 40 to CE, with no significant differences in demographic variables. IE group was enriched for patients in septic shock (87.7%, vs. 40 and 65%; p< 0.001), associated with higher mean lactate levels (65mg/dL, vs. 36 and 36.6mg/dL; p< 0.001) and pronounced positive fluid balance within the first 24h (5.73L, vs. 3.4 and 4.45L; p=0.019). 24.1%, 17.4%, and 7.7% of patients (IE, AE, CE, respectively) required RRT within 7d after admission (p=0.118). In contrast, there was a trend for a higher occurrence of persistent AKI in IE and CE (60.7 and 69.6%) compared to AE (42.8%; p=0.156). IE patients showed the highest early (7d) mortality of 15.8%, followed by 8.6% and 2.5% for AE and CE, respectively (p=0.084). Similar 30d mortality rates of 26.3 and 27.1% were observed for IE and AE, while mortality was low in CE (10.0%; p=0.078). Conclusions: Patients with IE exhibited the highest need for RRT accompanied by elevated early and delayed mortality. In contrast, CE patients - despite exhibiting a high incidence of persistent AKI – show the lowest incidences for all other clinical outcomes. Transcriptomic endotyping seems to be a promising strategy for renal risk refinement in future trials.