ALbumin To Enhance Recovery from severe Acute Kidney Injury (ALTER-AKI)

Background

Severe Acute Kidney Injury that necessitates renal replacement therapy (AKI-RRT) is a frequent complication of critical illness and portends severe outcomes: high morbidity, an approximately 50% risk of in-hospital death, and increased healthcare resource utilization. Although life-sustaining when needed, RRT itself may contribute to the poor outcomes associated with AKI-RRT. Since RRT treatments frequently cause hypotension, repeated episodes of kidney and other organ ischemia may occur during RRT. Hypotension during RRT is often triggered by fluid removal. At the same time, there is some evidence that more aggressive ultrafiltration could be beneficial in AKI-RRT.
Albumin is a protein that is the primary contributor to the colloid oncotic pressure maintaining the effective circulating volume (ECV) during RRT. Critically ill patients with AKI-RRT are nearly always hypoalbuminemic. Despite its high cost and limited evidence to support the practice, intravenous hyperoncotic albumin is commonly administered to patients with AKI-RRT in an effort to boost the colloid oncotic pressure and maintain the blood pressure while simultaneously facilitating fluid removal. Our group has found that many clinicians in Canada report prescribing intravenous hyperoncotic albumin in this context but there is a wide variation in practice. With a view to establishing better evidence related to this practice, our group recently completed a single-centre pilot, blinded, randomized, controlled trial that allocated patients to receive intravenous hyperoncotic albumin or saline (placebo) boluses during RRT treatments for AKI-RRT in ICU. The pilot study successfully confirmed the safety of intravenous hyperoncotic albumin in this setting as well as the feasibility of a larger trial with respect to recruitment, adherence to the intervention, and adequate follow-up.

Objectives

The objectives of this trial are to determine whether, in critically ill patients with AKI-RRT, randomization to receive intravenous hyperoncotic albumin 20-25% (100 mL X two doses) compared to control 0.9% saline boluses (100 mL X two doses) given during RRT sessions, leads to:

1.An increase in organ support-free days (primary outcome) at 28 days following initiation of RRT; and

2.An increase in RRT-free days (principal secondary outcome) at 28 days following initiation of RRT.

Study Population: Recruitment will begin at 5 centres across Canada, expanding to other centres in Canada and internationally with a planned enrollment of 1,096 participants.

Inclusion criteria (all need to be fulfilled for eligibility)
1) Age ≥ 18 years.
2) Admission to a critical care unit/intensive care unit (ICU) for ≥24 hours.
3) Receiving vasoactive therapy AND/OR undergoing mechanical ventilation (including non-invasive mechanical ventilation).
4) Initiation of RRT for management of AKI is imminently planned OR additional RRT sessions are imminently planned for patients who already received RRT during their ICU admission..

Exclusion criteria (any of the following factors will result in ineligibility)
1) Presence of a non-AKI indication that triggers RRT initiation or continuation (e.g. drug intoxication; treatment of hypothermia).
2) Known pre-hospitalization end-stage kidney disease.
3) Kidney transplant within the past 365 days.
4) Presence or clinical suspicion of renal obstruction, rapidly progressive glomerulonephritis, vasculitis, thrombotic microangiopathy or acute interstitial nephritis.
5) Advanced cirrhosis (Child Pugh class C [score 10-15]), spontaneous bacterial peritonitis or hepatorenal syndrome.
6) Acute peritoneal dialysis used as the initial RRT modality.
7) Contraindications to albumin:
a. Admitted with traumatic brain injury
b. Increased intra-cranial pressure in those with intra-cranial pressure monitoring.
c. Prior history of anaphylaxis to intravenous albumin.
d. Contraindication or known objection to albumin/blood product transfusions.
8) Already received more than 1 RRT session during ICU admission.
9) Lack of commitment to ongoing life support.

Interventions

Patients will be randomized to receive either intervention or control study fluids during all RRT treatments received in ICU for up to 14 days. The study fluid given to patients in the intervention arm will be intravenous hyperoncotic (20-25%) albumin. For patients in the control arm, the study fluid will be intravenous 0.9% saline. Study fluid will be administered with every ‘RRT session’ according to the RRT modality that is being used, as follows:

• Intermittent Hemodialysis (HD): 100 mL bolus of study fluid at initiation of HD treatments and another 100 mL given halfway through the ordered HD treatment duration. As most treatments are 4 hours, this will usually result in administration of the boluses at 0 and 2 hours into treatment.
• Sustained Low-Efficiency Dialysis (SLED) (also referred to as Hybrid RRT/Prolonged Intermittent RRT) : 100 mL bolus of study fluid at the start of SLED treatments and another 100 mL given halfway through the ordered SLED duration. As SLED treatments are typically 6 to 12 hours, this will usually result in administration of the boluses at 0 and 3-6 hours into treatment.
• Continuous RRT (CRRT): 100 mL boluses of study fluid given at the initiation of CRRT treatment (or at the time of randomization if already started on CRRT) and every 12 hours while they remain on CRRT (i.e. 24 hour sessions). To prevent confusion and missed doses, for any CRRT stoppage time less than 3 hours, albumin will continue to be given according to a q12h schedule (rather than every 12 hours on treatment) provided that ongoing CRRT is planned by the treating team.

The administered volume of study fluid (albumin or saline control) will be suggested to be removed via ultrafiltration with RRT at the discretion of the treating clinician.

As per usual care (and according to the RRT modalities available in the ICU which they are being treated in), patients may receive different forms of RRT at different times during their stay in ICU according to their hemodynamic stability and at the discretion of the treating team. For example, it is possible for a patient to start CRRT before transitioning to SLED and then transitioning to intermittent HD. It is also possible to start on intermittent HD and then transition to SLED or CRRT and then back. The study does not dictate which RRT modalities are used. The RRT modality that a patient is receiving on any given day will dictate how the intervention or control is administered during RRT, as described above. Interventions will be administered with every RRT ‘session’ (e.g. intermittent HD, SLED, 24 hours of CRRT) during the patient’s ICU admission in which they first initiated RRT, for up to 14 days after initiation of RRT.

All aspects of RRT (i.e. RRT initiation, modality selection, dose, anticoagulation, ultrafiltration goals, discontinuation) provided to participants in both treatment arms will be determined by an individual participant’s treating team and in accordance with the standard practices of the ICU in which they are receiving treatment. Recommendations will be provided against the use of non-study albumin during RRT however there will be no treatment restrictions.

Primary outcome
Organ support-free days through 28 days following enrollment. [Organ support-free days are defined as days that are both: 1) vasoactive therapy-free; AND 2) mechanical ventilation-free (including non-invasive ventilation). For patients who die within 28 days following randomization, organ support-free days are counted as -1.]

Secondary outcomes
1. RRT-free days through day 28. [For each patient, one point will be given for each calendar day that a patient does not receive any RRT. A -1 RRT-free day value will be assigned to patients who die within 28 days following randomization.] This is the Principal Secondary Outcome.
2. Vasoactive therapy-free days through day 28. [For patients who die within 28 days following randomization, vasoactive therapy-free days are counted as -1.]
3. Mechanical ventilation-free days through day 28 [For patients who die within 28 days following randomization, mechanical ventilation-free days are counted as -1.]
4. ICU-free days through day 28 [For patients who die within 28 days following randomization, ICU-free days are counted as -1.]
5. Death in ICU.
6. All-cause mortality at 28 days.
7. All-cause mortality at 90 days.
8. Death in ICU, at 28 days, and in-hospital.
9. RRT dependence at 90 days among surviving patients
10. Composite of death or RRT dependence at 90 days.
11. Estimated glomerular filtration rate among patients alive at Day 90.
12. Major adverse kidney outcomes, defined as death, RRT dependence or sustained reduction in kidney function (defined as eGFR < 75% baseline eGFR) at 90 days.
13. Hospitalization-free days through day 90.
14. EuroQoL EQ-5D-5L (a measure of health-related quality of life and patient utility) at day 90.
15. Occurrence of RRT-associated hypotension (for every RRT session in ICU after enrollment) (defined as: a drop in blood pressure during RRT requiring one of: initiation or increase in dose of a vasopressor during RRT session or premature discontinuation of RRT session due to hypotension).
16. Daily calculated net fluid balance to day 14 or ICU discharge.
17. Difference between ordered and achieved ultrafiltration for all intermittent HD / SLED treatments.
18. Daily sequential organ failure score (SOFA) score after enrollment (until ICU discharge or day 28.)
19. Health care costs through day 365. [captured using administrative data or hospital-captured case-costing data, where possible, and as part of a planned additional study]
20. Vital status and RRT-dependence at 365 days among survivors. [captured using administrative data, where possible, and as part of a planned additional study]

Implications
Intravenous hyperoncotic albumin may improve clinically important outcomes in critically ill patients who require RRT for severe AKI. By mitigating against hemodynamic instability provoked by RRT, it could prevent recurrent ischemia due to hypotension and reduce the duration for which patients require vasoactive therapy in ICU. Simultaneously, it may facilitate fluid removal via ultrafiltration with RRT and allow patients to wean more-quickly from ventilatory support and avoid other complications of prolonged fluid overload. If hyperoncotic albumin is efficacious, longer-term benefits with respect to survival and kidney recovery are likely to be evidenced more proximally with a reduction in organ support-free days (i.e. a composite measure of ICU-support in the form of vasoactive therapy and/or mechanical ventilation which also takes into account the potential impact of the intervention on short-term mortality). Intravenous hyperoncotic albumin is widely available and expensive ($71 per 100 mL bottle in Canada). Our group has previously shown that it is already often prescribed for Canadian patients with AKI-RRT although practices vary widely. Should intravenous hyperoncotic albumin be determined to be effective in improving clinically important outcomes, it is a treatment that could readily be broadly implemented for most patients with AKI-RRT. At the same time, if it is determined that it is ineffective then significant cost savings would result by limiting its use in this setting.

We aim to start enrolling patients locally in the summer of 2023 before expanding to other sites.