Restrictive Versus Liberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury

NCT05306964 | Terminated Results DMC

• 2 other identifiers: STUDY210800101R01DK128100-01A1
• Study Type: interventional
• Target: 99
• Locations: 1 country
• Sites: 2

Brief Summary

Critically ill patients with acute kidney injury and fluid overload who are frequently treated by fluid removal during dialysis are at an increased risk of complications and death. Both slower and faster rates of fluid removal may cause injury to the vital organs. This proposed clinical trial will examine the feasibility of restrictive compared with a liberal rate of fluid removal in order to develop effective treatments for fluid overload and to improve the health of critically ill patients.

Conditions

Acute Kidney Injury; Fluid Overload; Hypotension; Dialysis; Complications; Critical Illness

Keywords

Fluid overload; Acute kidney injury; Net ultrafiltration; Intensive care unit; Intradialytic hypotension; Complications; Feasibility Trial; Cardiac arrhythmias; Mortality; Dialysis dependence

Outcome Measures

Primary Outcomes (3)

• Delivered UFnet Rates.

  A minimum separation of 0.53-0.57 mL/kg/h in mean delivered UFnet rates between the two intervention arms.

  Until the end of continuous kidney replacement therapy or day 28, whichever occurs first.

• No. of Participants With Protocol Deviation.

  Protocol deviation defined as delivered UFnet rate that lies \>0.5 mL/kg/h outside of the target UFnet rate range for greater than six consecutive hours.

  Until the end of continuous kidney replacement therapy or day 28, whichever occurs first.

• Participant Recruitment/ICU/ 2 Months

  An enrollment rate of 1 patient per ICU per time period.

  24 months

Secondary Outcomes (9)

• Daily Fluid Balance (Average)

  Average daily fluid balance from enrollment to ICU discharge or until day 28, whichever occurs first.

• Cumulative Fluid Balance

  Daily from enrollment to ICU discharge or until day 28, whichever occurs first.

• Duration of Kidney Replacement Therapy

  Daily from enrollment to hospital discharge or until day 28, whichever occurs first.

• Duration of Mechanical Ventilation

  Daily from study enrollment to ICU discharge or until day 28, whichever occurs first.

• Organ Failure Free Days

  Daily from study enrollment to ICU discharge or until day 28, whichever occurs first.

Other Outcomes (21)

• No. of Intradialytic Hypotension Episodes

  From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.

• No. of Intradialytic Hypertension Episodes

  From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.

• No. of Episodes of Intradialytic Cardiac Arrhythmias

  From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.

Study Arms (2)

Restrictive UFnet Strategy

ACTIVE COMPARATOR

Fluid removal will be titrated to keep net ultrafiltration rate between 0.5-1.5 mL/kg/h

Procedure: Restrictive UFnet Rate Strategy

Liberal UFnet Strategy

ACTIVE COMPARATOR

Fluid removal will be titrated to keep net ultrafiltration rate between 2.0-5.0 mL/kg/h

Procedure: Liberal UFnet Rate Strategy

Interventions

Restrictive UFnet Rate Strategy PROCEDURE

In the restrictive group, the UFnet rate will be titrated between 0.5-1.5 mL/kg/h and maintained throughout fluid removal.

Restrictive UFnet Strategy

Liberal UFnet Rate Strategy PROCEDURE

In the liberal group, the UFnet rate will be titrated between 2.0-5.0 mL/kg/h and maintained throughout fluid removal.

Liberal UFnet Strategy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years or older
• Stage 3 acute kidney injury according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria
• Started or intending to start CKRT for volume management
• Attending intensivist or nephrologist intending to remove net fluid using CKRT for at least 48 hours

You may not qualify if:

• Respiratory distress due to pulmonary edema or fluid overload in unintubated patients
• Massive volume infusion (i.e., \>200 mL/h for \>6 hours of continuous infusion)
• No intention to remove net fluid as determined by attending intensivist or nephrologist
• Attending intensivist or nephrologist believes that the protocol will not be followed
• Continuous net fluid removal for \>48 hours prior to study enrollment
• Patients on chronic outpatient hemodialysis
• Patients with history of, or current admission for kidney transplantation
• Patients on comfort measures only orders.
• Moribund not expected to survive \>24 hours
• Confirmed pregnancy
• Patients treated with extracorporeal membrane oxygenation, ventricular assist device, or intra-aortic balloon pump
• Organ donors with neurological determination of death (i.e., brain dead donors)
• Drug overdose requiring CKRT for drug clearance
• Enrollment in a concurrent interventional clinical trial with direct impact on fluid balance (e.g., \>500 mL study drug administration)

Sponsors & Collaborators

• University of Pittsburgh: lead
• Mayo Clinic: collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (2)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15261, United States

Location

Related Publications (13)

• Murugan R, Kerti SJ, Chang CH, Gallagher M, Clermont G, Palevsky PM, Kellum JA, Bellomo R. Association of Net Ultrafiltration Rate With Mortality Among Critically Ill Adults With Acute Kidney Injury Receiving Continuous Venovenous Hemodiafiltration: A Secondary Analysis of the Randomized Evaluation of Normal vs Augmented Level (RENAL) of Renal Replacement Therapy Trial. JAMA Netw Open. 2019 Jun 5;2(6):e195418. doi: 10.1001/jamanetworkopen.2019.5418.

  PMID: 31173127 BACKGROUND

• Murugan R, Balakumar V, Kerti SJ, Priyanka P, Chang CH, Clermont G, Bellomo R, Palevsky PM, Kellum JA. Net ultrafiltration intensity and mortality in critically ill patients with fluid overload. Crit Care. 2018 Sep 24;22(1):223. doi: 10.1186/s13054-018-2163-1.

  PMID: 30244678 BACKGROUND

• Serpa Neto A, Naorungroj T, Murugan R, Kellum JA, Gallagher M, Bellomo R. Heterogeneity of Effect of Net Ultrafiltration Rate among Critically Ill Adults Receiving Continuous Renal Replacement Therapy. Blood Purif. 2021;50(3):336-346. doi: 10.1159/000510556. Epub 2020 Oct 7.

  PMID: 33027799 BACKGROUND

• Naorungroj T, Neto AS, Zwakman-Hessels L, Yanase F, Eastwood G, Murugan R, Kellum JA, Bellomo R. Early net ultrafiltration rate and mortality in critically ill patients receiving continuous renal replacement therapy. Nephrol Dial Transplant. 2021 May 27;36(6):1112-1119. doi: 10.1093/ndt/gfaa032.

  PMID: 32259841 BACKGROUND

• Naorungroj T, Neto AS, Zwakman-Hessels L, Fumitaka Y, Eastwood G, Murugan R, Kellum JA, Bellomo R. Mediators of the Impact of Hourly Net Ultrafiltration Rate on Mortality in Critically Ill Patients Receiving Continuous Renal Replacement Therapy. Crit Care Med. 2020 Oct;48(10):e934-e942. doi: 10.1097/CCM.0000000000004508.

  PMID: 32885938 BACKGROUND

• Murugan R, Ostermann M, Peng Z, Kitamura K, Fujitani S, Romagnoli S, Di Lullo L, Srisawat N, Todi S, Ramakrishnan N, Hoste E, Puttarajappa CM, Bagshaw SM, Weisbord S, Palevsky PM, Kellum JA, Bellomo R, Ronco C. Net Ultrafiltration Prescription and Practice Among Critically Ill Patients Receiving Renal Replacement Therapy: A Multinational Survey of Critical Care Practitioners. Crit Care Med. 2020 Feb;48(2):e87-e97. doi: 10.1097/CCM.0000000000004092.

  PMID: 31939807 BACKGROUND

• Murugan R, Bellomo R, Palevsky PM, Kellum JA. Ultrafiltration in critically ill patients treated with kidney replacement therapy. Nat Rev Nephrol. 2021 Apr;17(4):262-276. doi: 10.1038/s41581-020-00358-3. Epub 2020 Nov 11.

  PMID: 33177700 BACKGROUND

• Lumlertgul N, Murugan R, Seylanova N, McCready P, Ostermann M. Net ultrafiltration prescription survey in Europe. BMC Nephrol. 2020 Dec 1;21(1):522. doi: 10.1186/s12882-020-02184-y.

  PMID: 33256635 BACKGROUND

• Chen H, Murugan R. Survey of U.S. Critical Care Practitioners on Net Ultrafiltration Prescription and Practice among Critically Ill Patients Receiving Kidney Replacement Therapy. J Crit Care Med (Targu Mures). 2021 Nov 6;7(4):272-282. doi: 10.2478/jccm-2021-0034. eCollection 2021 Oct.

  PMID: 34934817 BACKGROUND

• Tehranian S, Shawwa K, Kashani KB. Net ultrafiltration rate and its impact on mortality in patients with acute kidney injury receiving continuous renal replacement therapy. Clin Kidney J. 2019 Dec 17;14(2):564-569. doi: 10.1093/ckj/sfz179. eCollection 2021 Feb.

  PMID: 33623680 BACKGROUND

• Naorungroj T, Serpa Neto A, Murugan R, Kellum JA, Bellomo R. Continuous Renal Replacement Therapy: The Interaction between Fluid Balance and Net Ultrafiltration. Am J Respir Crit Care Med. 2021 May 1;203(9):1199-1201. doi: 10.1164/rccm.202011-4097LE. No abstract available.

  PMID: 33513318 BACKGROUND

• Kitamura K, Hayashi K, Fujitani S, Murugan R, Suzuki T. Ultrafiltration in Japanese critically ill patients with acute kidney injury on renal replacement therapy. J Intensive Care. 2021 Dec 20;9(1):77. doi: 10.1186/s40560-021-00590-4.

  PMID: 34930481 BACKGROUND

• Murugan R, Chang CH, Raza M, Nikravangolsefid N, Huang DT, Palevsky PM, Kashani K; (RELIEVE-AKI) Study Investigators. Restrictive versus Liberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury (RELIEVE-AKI): a pilot clinical trial protocol. BMJ Open. 2023 Jul 7;13(7):e075960. doi: 10.1136/bmjopen-2023-075960.

  PMID: 37419639 DERIVED

MeSH Terms

Conditions

Acute Kidney Injury; Edema; Hypotension; Critical Illness; Arrhythmias, Cardiac

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Vascular Diseases; Cardiovascular Diseases; Disease Attributes; Pathologic Processes; Heart Diseases

Limitations and Caveats

First, clinicians may hold firm beliefs about UFnet titration, and their awareness of treatment assignment may have led to bias in UFnet titration, specifically not to increase UFnet rates in the liberal arm. Second, we did not assess circulating intravascular volume in UFnet titration as no technology has been validated for net fluid removal.

Results Point of Contact

• Title: Raghavan Murugan, MD, MS, FRCP, Principal Investigator
• Organization: University of Pittsburgh

muruganr@ccm.upmc.edu

412-647-8499

Study Officials

• Raghavan Murugan, MD, MS, FRCP

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Prospective, two-center, unblinded, parallel-group, 2-arm, comparative effectiveness, stepped-wedge cluster-randomized trial.

Study Record Dates

• First Submitted: March 2, 2022
• First Posted: April 1, 2022
• Study Start: July 5, 2022
• Primary Completion: June 17, 2024
• Study Completion: June 26, 2024
• Last Updated: August 29, 2025
• Results First Posted: August 29, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Beginning 9 months and ending 36 months after the publication of the primary trial manuscript.
• Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose.

Locations

US (2)