Background: Intravenous fluids are mainstay of management of acute kidney injury (AKI) after sepsis but can cause fluid overload. Recent literature shows that restrictive fluid strategy may be beneficial in some patients with AKI, however, identifying these patients is challenging. We aimed to develop and validate a machine learning algorithm to identify patients who would benefit from a restrictive fluid strategy. Methods and Findings: We included patients with sepsis who developed AKI within 48 hours of ICU admission and defined restrictive fluid strategy as receiving <500mL fluids within 24 hours after AKI. Our primary outcome was early AKI reversal within 48 hours of AKI onset, and secondary outcomes included sustained AKI reversal and major adverse kidney events (MAKE) at discharge. We used a causal forest, a machine learning algorithm to estimate individual treatment effects and policy tree algorithm to identify patients who would benefit by restrictive fluid strategy. We developed the algorithm in MIMIC-IV and validated it in eICU database. Among 2,091 patients in the external validation cohort, policy tree recommended restrictive fluids for 88.2%. Among these, patients who received restrictive fluids demonstrated significantly higher rate of early AKI reversal (48.2% vs 39.6%, p<0.001), sustained AKI reversal (36.7% vs 27.4%, p<0.001) and lower rates of MAKE by discharge (29.3% vs 35.1%, p=0.019). These results were consistent in adjusted analysis. Conclusion: Policy tree based on causal machine learning can identify septic patients with AKI who benefit from a restrictive fluid strategy. This approach needs to be validated in prospective trials.

GNN is a founder of Renalytix, Pensieve, Verici and provides consultancy services to AstraZeneca, Reata, Renalytix, Siemens Healthineer and Variant Bio, serves a scientific advisory board member for Renalytix and Pensieve. He also has equity in Renalytix, Pensieve and Verici. LC is a consultant for Vifor Pharma INC and has received honorarium from Fresenius Medical Care. JAK reports receiving consulting fees from Astute Medical/bioMerieux, Astellas, Alexion, Chugai Pharma, Novartis, Mitsubishi Tenabe and GE Healthcare and is a Full-time employee of Spectral Medical. All remaining authors have declared no conflicts of interest.

This work was supported by the National Institutes of Health (NIH) grants K08DK131286 awarded to A.S., R01DK108803, U01HG007278, U01HG009610, and U01DK116100 awarded to G.N.N. and T32DK007757 and TL1DK136048 awarded to W.O. The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study received approval from the Institutional Review Board at the Icahn School of Medicine at Mount Sinai (approval no. 19-00951).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes