This study will enroll adults aged 18 to 80 years diagnosed with sepsis due to a suspected or confirmed bacterial infection, within 7 days of being admitted to the hospital, and who have also developed acute kidney injury within 72 hours of the onset of sepsis. Eligible participants will be randomly assigned to receive either AZD4144 or a placebo intravenously once daily for the number of days specified in the CSP. During this Treatment Period, participants will undergo daily safety monitoring, as well as blood and urine sample collection and other assessments. After the Treatment Period, participants will continue to be monitored for safety and other assessments during each additional day they remain hospitalized (if applicable) as well as during up to 2 follow up visits after discharge. The main goal is to compare specific kidney function measurements between those participants receiving AZD4144 and those receiving the placebo.

This is a Phase IIa, randomised, double-blind, placebo-controlled, multicenter study that will be conducted in adult participants (aged 18-80) with sepsis-associated acute kidney injury (SA-AKI). Eligible participants must have sepsis secondary to suspected or confirmed bacterial infection requiring vasopressor or inotrope therapy, and AKI (KDIGO Stage ≥ 1) within a defined time frame of sepsis onset. Participants will be randomised in a 1:1 ratio to receive either intravenous AZD4144 or matching placebo once daily for a fixed treatment period. The study will be comprised of:

• A screening period
• A treatment period, during which participants receive intravenous AZD4144 or placebo daily according to the protocol dosing days.
• A follow-up period that will include daily assessments while still hospitalized and up to two additional outpatient visits at scheduled times after discharge.

Inclusion Criteria Age ≥ 18 to ≤ 80 years at the time of signing the informed consent. Participants who are admitted to an ICU or an equivalent critical-care unit.

Diagnosis of sepsis according to criteria defined by The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) based on:

A. Suspected or confirmed bacterial infection AND B. Acute increase of mSOFA score of 2 or more excluding renal component (change in score measured to account for participants that may meet mSOFA criteria from pre-existing organ dysfunction before the onset of infection).

Haemodynamic therapy:

A. 30 mL/kg or clinically appropriate volume resuscitation prior to randomisation.

B. Vasopressor and/or inotrope therapy for sepsis-induced hypotension (eg, norepinephrine [noradrenaline], epinephrine [adrenaline], phenylephrine, dopamine, dobutamine) for ≥ 4 hours.

Diagnosis of AKI, within 72 hours of sepsis diagnosis, with modified KDIGO Stage ≥ 1, defined as: Increase in SCr to ≥ 1.5 × baseline (outpatient [preferred] or admission pre-AKI reference). Timing of AKI diagnosis is defined as the time that the initial qualifying SCr was reported. AKI must persist after completion of initial volume resuscitation (30 mL/kg or as clinically indicated per investigator discretion).

Outpatient pre-AKI reference eGFR ≥ 30 mL/min/1.73 m2, if available within 2 weeks to 12 months prior to admission (preferred). If not available, admission pre-AKI reference eGFR ≥ 45 mL/min/1.73 m2 .

Body weight ≥ 40 kg or ≤ 125 kg. Female or male, assigned at birth, inclusive of all gender identities. All FOCBP must have a negative pregnancy test at the Screening visit (Visit 1).

Contraception:

A. Sexually active fertile male participants with partners of childbearing potential must adhere to the contraception methods detailed in CSP from the time of first administration of study intervention administration until 100 days after the last dose of study intervention.

B. FOCBP must not be lactating and must agree to use an approved method of highly effective contraception, as detailed in the CSP from the time of first administration of study intervention until 100 days after last dose of study intervention.

Capable of giving signed informed consent (participant or LAR). Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research.

Exclusion Criteria Any clinical evidence which in the investigator's opinion makes it undesirable for the potential participant to enrol in the study.

Known history of Stage 4 or 5 CKD with documented sustained eGFR < 30 mL/min/1.73 m2 prior to hospital admission.

Sepsis diagnosed > 7 days after hospital admission (to include from time of outside admission if patient transferred from another healthcare setting).

AKI attributed to causes other than sepsis, including but not limited to compromised renal perfusion-related causes (surgical complication, acute abdominal aortic aneurysm, dissection, renal artery stenosis, etc), glomerular disease, acute interstitial nephritis, and medication toxicity.

Evidence of recovery from AKI prior to randomisation defined as:

A. A reduction of SCr to less than 1.5 times reference SCr in the last available local SoC laboratory result before randomisation or B. A > 25% reduction in SCr from peak SCr after volume resuscitation prior to randomisation.

Expected survival from sepsis < 24 hours. Expected survival < 90 days due to chronic or pre-existing medical conditions other than SA-AKI Known history of renal transplant or bilateral nephrectomy. Permanent incapacitation. Incapacitation is defined as the inability to independently perform tasks essential to personal health and/or safety.

Active cancer or cancer in remission for less than 2 years. Known history of immunodeficiency disease or currently receiving immunosuppressant therapy for non-sepsis related disease.

Severe burns requiring ICU treatment. Sepsis attributed to confirmed or presumed fungal or viral infection at time of Screening.

Has advanced chronic liver disease, confirmed by a Child-Pugh score of 10-15 (Class C).

Known history of cerebrovascular accident within the last 90 days. Known history of heart failure with reduced ejection fraction with documented ejection fraction ≤ 20% before sepsis diagnosis.

Known hypersensitivity to iohexol or known history of severe adverse reaction to iodinated contrast media.

Participants with known medical or psychological condition(s), or who, in the judgement of the investigator, should not participate in the study if they are unlikely to comply with study procedures, restrictions, and requirements.

Current KRT (eg, continuous haemofiltration and haemodialysis/continuous kidney replacement therapy, intermittent haemodialysis, and peritoneal dialysis) or planned KRT (meaning KRT is scheduled, or the decision to initiate KRT has been made by the treating physician) at randomisation.

Currently receiving active treatment for malignancy.

Potential participants will be excluded if they have received a certain class of medication during the weeks before enrollment or are anticipated to require a specific class of medication during the trial duration.

Participants with a known hypersensitivity to AZD4144 or any of the excipients of the product.

Receipt of another IMP within 30 days, 5 half-lives, or the time frame of expected PD effect from most recent dose, whichever is longest.

Previous receipt of AZD4144. Active or planned treatment of sepsis with an extracorporeal haemoperfusion device.

Participation in any other concurrent ICU study which could impact participant clinical outcomes and confound results of this study to, including but not limited to volume resuscitation, vasopressor, or mechanical ventilation studies.

Presence of anuria (≥ 12 hours) at randomisation. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12-lead ECG, at Screening, as judged by the investigator.

Prolonged QTcF > 470 ms. Known history of QT prolongation associated with other medications that required discontinuation of that medication.

Congenital long QT syndrome. Known history of ST-elevation myocardial infarction or non-ST-elevation myocardial infarction, with or without intervention by percutaneous coronary intervention or coronary artery bypass grafting within the last 90 days.

Ventricular arrhythmia requiring treatment. Known or presumed latent or active tuberculosis. Acute pancreatitis with no established source of infection. Undergoing extracorporeal membrane oxygenation (ECMO) at randomisation. Neutropenia: ANC < 1.5 × 109/L. Admitting diagnosis of rhabdomyolysis. Admitting diagnosis of trauma with CK > 15000 U/L. Presumed nidus of infection in central nervous system. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

Previous randomisation in the present study. For females only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding.

First infusion of IMP unable to be started within 36 hours of AKI diagnosis. Presence of a do-not-resuscitate order.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. ''Yes", indicates that AZ is accepting requests for IPD, but this does not mean all requests will be approved.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Double-blind; Investigators, blinded Sponsor staff, site staff, and participants will remain blinded to each participant's assigned study intervention throughout the course of the study (with the exception of the site pharmacist(s) or designee preparing the IMP and unblinded Monitors/CRAs).