Restrictive Versus Liberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury (RELIEVE-AKI)

REstrictive Versus LIberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury

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.

Study Overview

• Status: Terminated
• Conditions: Critical Illness; Acute Kidney Injury; Hypotension; Fluid Overload; Dialysis; Complications
• Intervention / Treatment: Procedure: Restrictive UFnet Rate Strategy; Procedure: Liberal UFnet Rate Strategy

Detailed Description

"Net ultrafiltration (UFnet)," also known as net fluid removal during kidney replacement therapy, has been used in the treatment of fluid overload among critically ill patients with acute kidney injury (AKI) for more than seven decades. However, the optimal rate of fluid removal (i.e., UFnet rate) remains uncertain, complications such as hypotension and cardiac arrhythmias occur frequently, and more than 40% of patients die. Observational studies in critically ill patients receiving continuous kidney replacement therapy (CKRT) show that UFnet rate has a "J" shaped association with mortality with both slower and faster UFnet rates associated with increased risk of death compared with moderate UFnet rates.

The overall objective of this randomized trial is to establish the feasibility of maintaining patients in the restrictive UFnet rate strategy during treatment with CKRT. The investigator's central hypothesis is that a restrictive UFnet rate strategy embracing a "slow and steady" approach to fluid removal is associated with fewer complications, including cardiac arrhythmias, hypotension, and death, compared with a more liberal "sprint and pause" strategy among critically ill patients.

The trial is a prospective, two-center, unblinded, parallel-group, 2-arm, comparative effectiveness, stepped-wedge cluster-randomized trial among 112 critically ill patients with AKI treated with CKRT in 10 ICUs across two hospital systems. The trial will be conducted at 5 ICUs at University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania, as well as 5 ICUs at Mayo Clinic, Rochester, Minnesota. ICUs will be randomized 1:1 to either a restrictive or a liberal UFnet rate strategy. During the first six months, all ICUs will continue with a liberal UFnet rate strategy. Every two months thereafter or when 10 patients have been enrolled, whichever occurs first, one ICU will be randomized to deploy the restrictive UFnet rate strategy.

In the liberal group, the UFnet rate will be titrated between 2.0-5.0 mL/kg/h and maintained throughout fluid removal. In the restrictive group, the UFnet rate will be titrated between 0.5-1.5 mL/kg/h and maintained throughout fluid removal. The UFnet rates used in both strategies are used in current clinical practice.This feasibility trial will be used to support the rationale and design of a future multicenter phase III randomized trial to examine the effects of alternative UFnet rate strategies on patient-centered clinical outcomes.

Amendment changes- The "Delivered UFnet rates" outcome measure was amended based on a new calculation of effect size when we lowered the sample size from 144 patients to 112 patients in the trial.

The Participant Recruitment Rate Over 21 Months" outcome measure was based on a new sample size estimation when we lowered the sample size from 144 patients to 112 patients in the trial due to slow rate of enrollment in the trial.

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Restrictive UFnet Strategy; Fluid removal will be titrated to keep net ultrafiltration rate between 0.5-1.5 mL/kg/h	Procedure: Restrictive UFnet Rate Strategy; In the restrictive group, the UFnet rate will be titrated between 0.5-1.5 mL/kg/h and maintained throughout fluid removal.
Active Comparator: Liberal UFnet Strategy; Fluid removal will be titrated to keep net ultrafiltration rate between 2.0-5.0 mL/kg/h	Procedure: Liberal UFnet Rate Strategy; In the liberal group, the UFnet rate will be titrated between 2.0-5.0 mL/kg/h and maintained throughout fluid removal.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily Fluid Balance (Average)	Patient daily fluid balance will be measured while on continuous kidney replacement therapy and reported as average across all study days.	Average daily fluid balance from enrollment to ICU discharge or until day 28, whichever occurs first.
Cumulative Fluid Balance	Patient cumulative fluid balance will be measured while on continuous kidney replacement therapy.	Daily from enrollment to ICU discharge or until day 28, whichever occurs first.
Duration of Kidney Replacement Therapy	The number of days the patient received kidney replacement therapy while in the hospital.	Daily from enrollment to hospital discharge or until day 28, whichever occurs first.
Duration of Mechanical Ventilation	The number of days the patient received mechanical ventilation while in hospital.	Daily from study enrollment to ICU discharge or until day 28, whichever occurs first.
Organ Failure Free Days	The no. of days the patient remained free of organ failure while in the ICU.	Daily from study enrollment to ICU discharge or until day 28, whichever occurs first.
ICU Length of Stay	The number of days patients need to stay in the ICU	Daily from study enrollment to ICU discharge or day 28, whichever occurs first.
Hospital Length of Stay	The number of days patients need to stay in the hospital	Daily from study enrollment to hospital discharge or day 28.
Hospital Mortality	The proportion of patients who died while in the hospital.	From study enrollment to hospital discharge or day 28, whichever occurs first.
Dependence on Kidney Replacement Therapy	The proportion of patients who were on dialysis at hospital discharge.	From study enrollment until hospital discharge or day 28, whichever occurs first.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
No. of Intradialytic Hypotension Episodes	Intradialytic hypotension will be defined as a new mean arterial pressure <65 mmHg, systolic blood pressure <90 mmHg or a decline in systolic blood pressure >40 mmHg, and/or a >30% increase in dose of existing vasopressors, initiating a new vasopressor, or administration of fluid bolus with a goal to maintain mean arterial pressure >=65 mmHg, systolic blood pressure >=90 mmHg.	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Intradialytic Hypertension Episodes	Intradialytic hypertension will be defined as new onset systolic blood pressure >=160 mmHg or mean arterial pressure >=80 mmHg for more than 1 hour in the absence of any vasopressor or inotrope use.	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28.
No. of Episodes of Intradialytic Cardiac Arrhythmias	New onset intradialytic cardiac arrhythmias including supraventricular tachycardia, bradycardia, atrial fibrillation, ventricular tachycardia, ventricular fibrillation, asystole/pulseless electrical activity will be diagnosed as per American Heart Association.	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants Who Receive UFnet Rates Higher Than the Assigned Intervention Arm for Treatment of Fluid Overload Emergencies.	No. of participants in whom emergent use of UFnet rates higher than the assigned treatment arm for more than 3 consecutive hours will be noted.	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With Severe Hypophosphatemia	Hypophosphatemia defined by serum phosphate <0.5 mg/dL	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With Severe Hypokalemia	Hypokalemia defined by serum potassium <3.0 mg/dL	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With Severe Hypocalcemia	Hypocalcemia defined by serum calcium <1.90 mg/dL or ionized calcium <0.90 mmol/L	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Episodes of Stopping of CKRT System Due to Hemofilter Clotting or Clogging.	Stopping of CKRT system due to filter clotting and/or clogging.	From study enrollment until termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With Discontinuation of Fluid Removal Due to Hemodynamic Instability.	No. of participants in whom fluid removal is stopped due to hemodynamic instability such as intradialytic hypotension, cardiac arrhythmias, or cardiac arrest.	From study enrollment until termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants in Whom Surgical Wounds Are Left Open After Surgery Due to Tissue Edema.	This will be determined as per the primary surgeon. Abdominal wounds left open for a second look or for abdominal re-exploration will not be counted unless there is concurrent tissue edema precluding abdominal closure.	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With New Organ Dysfunction as Assessed by Change in Sequential Organ Failure Assessement (SOFA) Scoring System From Baseline.	New organ dysfunction will be assessed by changes in SOFA scores from the baseline across the five organ systems of central nervous system, cardiovascular, respiratory, coagulation, and liver.	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With Worsening of Systolic or Diastolic Cardiac Function on Echocardiogram From Baseline.	Changes in transthoracic echocardiogram will be assessed from baseline (if available)	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With Worsening of Pulmonary Edema on Chest X Ray and/or CT Scan Based on Radiologist Report.	Changes in chest X ray and CT scan will be assessed from baseline (if available).	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With Worsening of Ileus on Abdominal X Ray and/or CT Scan Based on Radiologist Report.	Changes in abdominal X ray and CT scan will be assessed from baseline (if available)	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With Bowel Ischemia or Anastomotic Breakdown Based on Intraoperative Findings.	Intraoperative findings of bowel ischemia or anastomotic breakdown will be noted as determined by the surgeon (if available).	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With Pressure Ulceration Per Nursing Records.	No. of participants with new diagnosis of pressure ulcerations as documented by the nursing staff in the electronic medical record (if available)	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With New Wound Infection Per Nursing Records.	No. of participants with new diagnosis of wound infection as documented by the nursing staff in the electronic medical record (if available)	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With New Arterial and/or Deep Vein Thrombosis as Assessed by Doppler Studies.	New arterial thrombosis or deep vein thrombosis as assessed by doppler study (if available)	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With Severe Anemia Requiring Red Cell Transfusions.	Participants with severe anemia requiring red cell transfusions (if available).	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With Severe Thrombocytopenia Requiring Platelet Transfusions.	No. of participants with severe thrombocytopenia requiring platelet transfusions (if available).	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.
No. of Participants With New Secondary Infections.	New diagnosis of secondary infections occurring after initiation of study intervention will be collected based on culture data, antibiotic use and suspected sepsis as per clinician judgment (if available).	From study enrollment until 24 hours after termination of continuous kidney replacement therapy or day 28, whichever occurs first.

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: Mayo Clinic; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Raghavan Murugan, MD, MS, FRCP, University of Pittsburgh

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2022
• Primary Completion (Actual): June 17, 2024
• Study Completion (Actual): June 26, 2024

Study Registration Dates

• First Submitted: March 2, 2022
• First Submitted That Met QC Criteria: March 22, 2022
• First Posted (Actual): April 1, 2022

Study Record Updates

• Last Update Posted (Estimated): August 29, 2025
• Last Update Submitted That Met QC Criteria: August 8, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Intensive care unit; Complications; Mortality; Intradialytic hypotension; Acute kidney injury; Fluid overload; Cardiac arrhythmias; Feasibility Trial; Net ultrafiltration; Dialysis dependence
• Additional Relevant MeSH Terms: Urogenital Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Heart Diseases; Disease Attributes; Metabolic Diseases; Chemically-Induced Disorders; Renal Insufficiency; Water-Electrolyte Imbalance; Poisoning; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Critical Illness; Acute Kidney Injury; Hypotension; Arrhythmias, Cardiac; Water Intoxication
• Other Study ID Numbers: STUDY21080010; 1R01DK128100-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The RELIEVE-AKI study investigators will review the request for data from other investigators. The investigators will execute a data-sharing agreement with the University of Pittsburgh to share de-identified data with other investigators for research purposes only. The data-sharing agreement will ensure: i.) a commitment to using the data only for research purposes and not to identify any individual participant; ii.) a commitment to securing the data using appropriate computer technology; and iii.) a commitment to destroying or returning the data after analyses are completed on a specific date. The investigators will not release any patient identifiers in any of the data files shared with other researchers. The investigators will also require appropriate confidentiality agreements and approvals from the Institutional Review Boards of other investigators before the data are shared.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months after the publication of the primary trial manuscript.
• IPD Sharing Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No